Frontiers in Nephrology: Heterologous Immunity, T Cell Cross-Reactivity, and Alloreactivity
Liisa K. Selin and
Michael A. Brehm
Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts
Correspondence: Dr. Liisa K. Selin, Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. Phone: 508-856-3039; Fax: 508-856-0019; E-mail: liisa.selin{at}umassmed.edu
Established memory T cell responses to a previously encounteredpathogen can have a major impact on the course and outcome ofa subsequent infection with an unrelated pathogen. This phenomenon,known as heterologous immunity, is dependent on the sequenceof infections and can be either beneficial or detrimental tothe host. Examples of heterologous immunity between unrelatedviruses and alloantigens are mounting, and the role of cross-reactiveT cells both in the pathogenesis of infections and in transplantrejection is now being explored. Memory T cells seem to be partof a continually evolving interactive network in which witheach new infection, an alteration in the frequencies, distributions,and activities of memory cells is generated in response to previousinfections and alloantigens.
ALTERATIONS OF IMMUNE T CELL RESPONSES BY HETEROLOGOUS IMMUNITY
The significance and characteristics of memory CD8 T cells inviral infections have been extensively studied. In many of thesestudies of T cell memory, experimental viral immunologists goto great lengths to ensure that their animal colonies are freeof endogenous pathogens to design reproducible experiments.These experimental results are then proposed to provide thebasis for our understanding of human immune responses to viruses.Although these findings can be enlightening, humans are notimmunologically naïve, and they often have memory T cellpopulations that can cross-react with and respond to a new infectiousagent or cross-react with alloantigens and influence the successof tissue transplantation. When activated, these cross-reactiveT cells can modulate the immune response and outcome of subsequentheterologous infections, a phenomenon we have termed heterologousimmunity.
Reports of pathogen-specific memory CD8 T cells recognizingcross-reactive epitopes on different proteins of the same pathogenor proteins from closely related or totally unrelated pathogensare increasing.1 Perhaps it is not surprising to observe cross-reactiveT cell responses directed at evolutionarily conserved siteswithin virus groups, such as different strains of influenzavirus2–4 or dengue virus5,6 or conserved sites betweendifferent members of the same virus group, such as hantaviruses,7arenaviruses,8 and flaviviruses.9 However, examples of cross-reactiveT cell responses involving completely unrelated viruses suchas lymphocytic choriomeningitis virus (LCMV) and vaccinia virus(VV),10,11 influenza virus and hepatitis C virus (HCV),12 influenzavirus and Epstein-Barr virus (EBV),13 influenza virus and HIV,14and human papillomavirus and coronavirus,15 have now also beenshown. These cross-reactive T cell responses are more frequentlyobserved once memory T cell populations have been generatedas a result of increased frequency and higher activation stateof memory T cells.16–18 When cross-reactive immune responsesare present, they can alter T cell dynamics and have considerableconsequences on the pathogenesis of infection and either inhibitor enhance the replication of a newly encountered heterologousvirus.19–22 They may have a significant impact on autoimmunediseases that have historically been associated with viral infections.23They can also have a significant impact on allospecific T cellactivity before and after transplantation.24,25 It is likelythat an individual's history of virus infections and the uniquecomposition of the cross-reactive memory T cell pool may eitherinitiate or reactivate T cells with alloreactive potential duringtransplantation.
CROSS-REACTIVITY, IMMUNODOMINANCE, AND T CELL RECEPTOR NARROWING
The CD8 T cell memory pool created after a virus infection hasa distinct hierarchy of dominant and subdominant epitope-specificresponses in a naïve host.26 This immunodominance hierarchyis regulated by various parameters, including the efficiencyof processing and presentation of the peptide, the affinitybetween peptide and the MHC I, the availability of T cells withT cell receptors (TCR) that recognize the peptide–MHCcomplex, and the competition between T cells for domains onthe antigen-presenting cell.27
Public versus Private Specificity
T cells that are involved in many epitope-specific responsesmaintain distinct amino acid motifs in the TCR CDR3 betweenclonotypes and between different individuals, suggesting thatthese sites are required for the TCR to bind to the MHC-ligandstructure. For example, in the human HLA-A2–restrictedinfluenza A M1–58 V17 response, the amino acid motif IRSSis common,28 and in the allospecific H2-Kd–restrictedHLA-CW3 Vb10 response in DBA/2 mice, SxG in the first threepositions of the CDR3 region is a common motif.29 These similaritiesbetween individuals in V usage and amino acid motifs, as wellas conservation of immunodominance hierarchies, can be thoughtof as the public specificities of epitope-specific T cell responses.However, within these public motifs, there can be tremendousdiversity in the TCR repertoire between individuals.29–32The TCR on the antigen-specific T cell clones are unique tothe individual, and these unique regions have been referredto as the "private specificity" for that epitope-specific response.This variation is probably a consequence of the random stochasticprocess of TCR rearrangement in the thymus, which results invariations in the naïve peripheral TCR repertoire, andof the random stochastic process whereby a T cell encountersan antigen-presenting cell presenting its cognate ligand.33
Cross-Reactive Memory T Cells Alter Subsequent Immune Repertoires
Because of their high frequency and enhanced activation state,cross-reactive memory CD8 T cells have an advantage over naïveT cells, leading to an alteration in the hierarchy of T cellresponses, as seen in sequential heterologous virus infectionsof mice with distantly related arenaviruses.8 Individual LCMV-immunemice challenged with VV varied in proliferative expansions ofT cells specific to three different LCMV epitopes: NP205 to212, GP34 to 41, and GP118 to 125.10 This finding reflectedthe private specificities of the memory TCR repertoires thatare unique to each individual mouse. T cell cross-reactivityinvolving two epitopes can select for a very small subset ofthe cross-reactive T cell population, leading to a substantialnarrowing of the TCR repertoire (Figure 1).34 This narrowingof the repertoire had different patterns between individuals,reflecting the private specificities of the immune system thatdeveloped after the primary infection.
Figure 1. Cross-reactive responses are more restricted at the proliferation than at the effector level, resulting in a narrowed T cell receptor (TCR) repertoire. The PV-NP205 memory repertoire has co-dominance of Vb5 (green dots) and VB16 (red dots). When these cells are stimulated in vitro with the cross-reactive LCMV NP205 peptide, the majority of the memory cells are functionally cross-reactive and produce IFN-. However, if this mouse is challenged with LCMV infection, then there is narrowing of the repertoire, with only the low-frequency Vb12 clones (yellow dots) growing out; in this case when the Vb12 clones are subcloned and the CDR3 region is sequenced, it is found to be dominated by a single clonotype.
CROSS-REACTIVITY AND HETEROLOGOUS IMMUNITY: A BALANCE BETWEEN PROTECTION AND PATHOLOGY
Memory T cells that are cross-reactive with a heterologous viruscan provide partial protective immunity and, in experimentalmodels, can be the difference between life and death in theinfected host.19,20,35,36 Experimental model systems have shownthat T cells not only mediate protective immunity but also mediatesubstantial immunopathology.37–42 LCMV-immune mice displayeddramatically altered pathology upon VV infection, although viralload was decreased. LCMV-specific T cell infiltration and inductionof panniculitis presenting as necrosis of visceral fat occurredin intraperitoneal infections19 and bronchiolitis obliterans,obstruction of bronchioles by fibrin and inflammatory cells,in respiratory infections.20 In humans, erythema nodosum, themost common form of panniculitis, and bronchiolitis obliteransare diseases of unknown cause but can be seen in some viraland bacterial infections and are also associated with autoimmunediseases.43–45 Erythema nodosum has been observed aftervaccination for smallpox or hepatitis B. The development ofbronchiolitis obliterans in lung allografts is associated withtransplant rejection.45 Influenza-immune mice that had augmentedviral replication upon LCMV or murine cytomegalovirus (MCMV)infection also developed a severe consolidating mononuclearpneumonia with evidence of bronchiolization instead of the usualmild mononuclear infiltrate observed in acute MCMV infectionof naïve mice. Bronchiolization involves bronchiolar-likecells’ replacing normal alveolar epithelium and is thoughtto be an indicator of lung repair.46
HETEROLOGOUS IMMUNITY AND ALTERED PATHOLOGY IN HUMANS
Manifestations of heterologous immunity may therefore be a contributingfactor in the variations observed in human disease pathogenesisthought previously to be affected only by genetic differences,the physiologic condition of the patient, or the inoculationroute and dosage. Cross-reactive T cell responses and heterologousimmunity remind us of the phenomenon of "original antigenicsin," which was first described for B cell responses againstinfluenza virus subtypes.47 Different strains and variants ofinfluenza virus are cross-reactive at the T cell level, leadingto speculations that these cross-reactive cells may be involvedin the pathogenesis of influenza virus infections.2–4Also, infection with one dengue virus serotype generates CD8T cells with a higher avidity to a second and previously encountereddengue virus, suggesting that cross-reactive memory CD8 T cellspreferentially expand over T cells with greater avidity to theserotype, causing infection.5,48 These lower avidity cross-reactiveT cells may lead to a more severe disease outcome, such as hemorrhagicfever, observed in subsequent infections with different denguevirus serotypes.
EBV and Acute Infectious Mononucleosis
Many viral infections, such as measles, mumps, chickenpox, andEBV, present with more severe symptoms in teenagers and youngadults than in young children. A massive CD8 T cell responseis pathognomic of infectious mononucleosis, and the differencebetween a clinical and an asymptomatic acute EBV infection isthe magnitude of the T cell response, not the viral load.49These older individuals have a longer history of infectionsand presumably a more complex pool of memory cells than youngchildren.50 A subset of T cells directed against a major HLA-A2.1restricted immunodominant EBV epitope, BMLF-1280, can cross-reactwith the invariant HLA-A2.1–restricted influenza A virusepitope M158.13 Activation of these cross-reactive T cells wasobserved in some but not all patients with acute mononucleosis,perhaps again reflecting private specificities in the host response.13Because of the large size of its genome, EBV likely presentsan extensive pool of potential CD8 T cell epitopes that couldactivate other cross-reactive memory CD8 T cells of differentspecificities.
Analyses of the M158 TCR repertoire from two individuals whoexperienced EBV-associated acute infectious mononucleosis revealeda substantially different hierarchy of J usage than in healthyinfluenza A immune donors. This suggests that a skewed subsetof the M158-specific TCR repertoire, probably those cross-reactivewith EBV, was being stimulated to proliferate. It is interestingthat these cross-reactive T cells behaved differently in theirfunctional responses to each ligand (Figure 2). Some cross-reactivecells bound both tetramers and produced TNF-, IFN-, and macrophageinflammatory protein 1 (MIP-1) to both ligands; some bound onlyone tetramer but produced TNF-, IFN-, and MIP-1 to the alternateligand; and some bound only one tetramer but were able to produceonly MIP-1 to the alternate ligand. It seems that how a cross-reactiveT cell interacts with its alternative ligand is highly variableand that functional patterns of T cell cross-reactivity areindeed heterogeneous. Multiple techniques are required to detectT cell cross-reactivity, including tetramer staining and differentfunctional assays. A potentially important factor in TCR interactionwith its ligand is TCR avidity. The cross-reactive interactioncould be too weak to bind tetramer stably but be sufficientto induce a distinct hierarchy of cytokine production.13,51
Figure 2. Cross-reactive FLU-M1–and EBV-BMLF1–specific T cells demonstrate differential functional profile to either peptide. A CD8 T cell line that was derived from a patient with acute infectious mononucleosis and was stimulated with both peptides simultaneously during culture increased the frequency of the double-tetramer–positive cross-reactive T cell population. Gating on this cross-reactive population and assessing the production of cytokines demonstrated a differential hierarchy of responsiveness to the FLU-M1 peptide (macrophage inflammatory protein 1 [MIP-1] > IFN- > TNF-). These cross-reactive cells produced all three cytokines efficiently to the EBV-BMLF1 peptide.
HCV and Fulminant Hepatitis
There is extreme variability in the pathogenesis of HCV in humans,ranging from asymptomatic to fulminant and from sterilizingto persistent infections.52 HCV encodes an HLA-A2–restrictedepitope (NS31073 to 1081) that shares six of eight amino acidswith the influenza epitope (NA231 to 239), and T cells frominfluenza-immune individuals with no evidence of a past HCVinfection can often respond to the HCV epitope in vitro.12 Manypeople may be partially immune to HCV as a consequence of thiscross-reactivity. However, two patients who developed fulminantnecrotizing hepatitis upon HCV infection were noted to havea highly narrowed focusing to this cross-reactive T cell responsebetween influenza and HCV.53 This study demonstrates that, asin the mouse studies, cross-reactive T cell responses can beassociated with enhanced immunopathology.
The principles of heterologous immunity are also applicablefor the induction of immune responses against foreign or allogeneicantigens. The alloreactive T cell repertoire in humans who havenever been exposed to alloantigens contains cells of both naïveand memory phenotypes.54,55 The presence of these memory T cellssuggests that alloreactive T cells are activated by past encounterswith environmental antigens. Cross-reactivity is an importantmechanism for heterologous immunity in the context of virus-specificimmune responses and also contributes to the activation of alloreactiveT cells by unrelated antigens.8,10,19,24,36,56–64 Theunexpected activation of alloreactive T cell responses by heterologousimmunity is a significant barrier for the transplantation offoreign organs and for the use of co-stimulation blockade protocols.65–67
RAPID IDENTIFICATION OF NAïVE ALLOREACTIVE T CELLS DIRECTLY EX VIVO
Current protocols to examine alloreactive T cell responses directlyex vivo measure effector functions such as IFN- production andcytotoxicity that are not detectable in naïve T cells.54,68–72Although these function-based assays are sensitive tools toidentify effector and memory T cells, they are not optimal forthe rapid detection of naïve-phenotype alloreactive T cells.We have shown that naïve T cells (CD11alow and CD44low)produce TNF but not IFN- within 4 h of TCR engagement.73 Usingthis unique cytokine profile (TNF+/IFN-–) as a marker,we were able to detect naïve alloreactive T cells aftera short in vitro stimulation with allogeneic cells.74 This rapidproduction of TNF was used for the reproducible quantificationof naïve alloreactive T cells from both mice and humansdirectly ex vivo, and the frequency of TNF-producing alloreactiveT cells detected ex vivo correlated with the ability of miceto reject implanted allogeneic cells. Moreover, the TNF assayallowed naïve phenotype T cells (TNF+/IFN-–/CD11alow)to be differentiated from effector/memory alloreactive T cells(TNF+/IFN+/CD11ahigh) that were generated by previous exposureto alloantigens and from tolerized alloreactive responses (TNF–/IFN-–).74The clinical application of the TNF assay may allow the identificationof transplant recipients who have low levels of T cell reactivityagainst a specific donor tissue and thereby minimize the requirementsfor long-term immunosuppression. In addition, this assay willprovide us with unique insights into the alterations that occurin the alloreactive T cell repertoire after viral infectionsand the induction of tolerance by co-stimulation blockade.
VIRAL INFECTIONS ACTIVATE ALLOREACTIVE T CELL RESPONSES
The presence of memory alloreactive T cells in humans who havenever been exposed to alloantigens may be attributed to pastviral and bacterial infections.54,55 Studies from our laboratoryhave shown that C57BL/6 mice that are acutely infected withLCMV generate effector CD8 T cells that recognize a broad rangeof allogeneic haplotypes.24,62,75,76 The alloreactive CD8 Tcells activated by LCMV displayed allospecific cytotoxic activityand produced IFN- after stimulation with alloantigens. AllospecificCD8 T cell cytotoxicity is also detectable in mice that areacutely infected with Pichinde virus (PV), VV, and MCMV andin humans who are infected with EBV and have developed acuteinfectious mononucleosis.58,76–78 Importantly, the alloreactiveCD8 T cells that are activated during acute infection are maintainedinto memory, indicating that viral infections may account forthe detection of memory alloreactive T cells in humans.24,62The activation of alloreactive T cells by infection and theirsurvival into memory have significant long-term implicationsfor the transplantation of foreign tissues and for the inductionof tolerance against alloantigens.
The virus-induced activation of alloreactive cytotoxic T cellssuggests that an acute infection would precipitate the rapidrejection of foreign tissue grafts. In humans, herpes virusinfections have been associated with the rejection of transplantedtissues.79,80 Using an in vivo cytotoxicity assay, we have shownthat viral infections induce a CD8 T cell–mediated rejectionof allogeneic implants.81 For evaluation of the rejection ofallogeneic implants, carboxyfluoroscein diacetate-succinimidylester (CFSE)-labeled allogeneic splenocytes (H2d and H2k) wereadoptively transferred into either naïve or infected C57BL/6mice (H2b), and their survival relative to co-transferred syngeneicsplenocytes was assessed 20 h later. Because the in vivo cytotoxicityassay also detects natural killer cell–mediated rejectionof allogeneic splenocytes,81,82 studies to examine T cell–dependentmechanisms were done in mice that were depleted of natural killercells. CD8 T cell–mediated rejection of H2d and H2k splenocyteswas detectable as early as 1 d after infection with either LCMVor PV, and this virus-induced rejection of the allogeneic populationsreached maximum levels in mice that were infected for 3 d.81These results indicate that the alloreactive T cells that areactivated by a viral infection will mediate the rapid rejectionof allogeneic tissues.
Cross-Reactivity between Virus-Specific T Cells and Alloantigens
The promiscuous nature of antigen recognition by the TCR enablesvirus-specific CD8 T cells to cross-react with antigens derivedfrom unrelated pathogens and immunogens.83 Numerous studieshave demonstrated that virus-specific CD8 T cells directly recognizealloantigens, and this cross-reactivity may account for theactivation of allospecific T cells after infection. Experimentsin our laboratory have shown that short-term LCMV-specific CD8T cell clones that are generated from infected mice recognizeboth LCMV-infected cells and allogeneic cell lines.62 This findingis in agreement with previous and more recent studies demonstratingthat CD8 T cell lines specific for influenza virus, Sendai virus,and vesicular stomatitis virus (VSV) for mice and human CD8T cell lines specific for EBV and HSV recognize alloantigens.56,57,63,64,84Recent experiments have also shown that human CD4 T cell linesspecific for CMV or EBV cross-react with allogeneic MHC classII.85,86 In detailed studies of cross-reactivity during an acuteinfection of C57BL/6 mice (H2b), we showed that LCMV-specificCD8 T cells defined by MHC-tetramer staining produce IFN- afterin vitro stimulation with allogeneic cell lines but not withsyngeneic cell lines (Figure 3).24 This cross-reactivity wasbroad based in that a proportion of each of the four epitope-specificresponses (GP33, GP276, NP205, and NP396) examined recognizedH2d antigens. However this cross-reactivity also showed selectivityin that different proportions of the epitope-specific cellsrecognized H2d antigens. The selective nature of cross-reactivitywas also demonstrated in the recognition of H2k antigens thatagain was broad based but more restricted as only two of thefour epitope-specific populations were activated by H2k.24 Together,these results indicate that virus-specific T cells broadly cross-reactwith alloantigen, but the selective nature indicates that thiscross-reactivity is an antigen-driven phenomenon and is dictatedby the diversity of TCR expressed by antigen-specific T cells.
Figure 3. Cross-reactivity between virus-specific CD8 T cells and alloantigens. (A) CD8 T cells were recovered from B6 mice that were infected 8 d earlier with LCMV. (B) CD8 T cells were incubated with allogeneic cell lines (either H2d or H2k) for 5 h and then examined for the production of IFN- by intracellular cytokine assay. Alloreactive T cells produced IFN- after stimulation with alloantigen. (C) Virus-specific CD8 T cells were identified by staining with MHC class I tetramers loaded with LCMV-derived peptides. Cross-reactive cells were defined as both IFN- and tetramer positive.
HETEROLOGOUS IMMUNITY AND TRANSPLANTATION TOLERANCE
The prolonged survival of foreign tissues in transplant recipientsrequires a long-term state of generalized immunosuppression.87,88As an alternative to the use of immunosuppressive therapiesin transplant patients, novel protocols that specifically inducetolerance against donor antigens have been developed.89 Theproductive activation of T cells requires both TCR engagement(signal 1) and co-stimulation (signal 2), and therefore a blockadeof co-stimulatory signals during exposure to antigen will specificallytolerize the responding T cells.90–92 The blockade ofco-stimulatory signals, such as CD28:CD80 and CD40L:CD40 pathways,induces tolerance to alloantigens and allows long-term allograftsurvival.93–98 Co-stimulatory blockade establishes antigen-specifictolerance by the physical deletion of alloreactive T cells,by the induction of anergy, and by the induction of immunoregulatorymechanisms (Figure 4A).99–101 Recent work from our laboratoryand elsewhere has demonstrated that both viral and bacterialinfections have unexpected consequences for the use of co-stimulationblockade to induce tolerance against alloantigens.24,25,102–105
Figure 4. Viral infections abrogate the induction of transplant tolerance. (A) Co-stimulation blockade (donor-specific transfusion [DST] and anti-CD154) induces tolerance to alloantigens by early deletion of alloreactive T cells, and tolerance is maintained by induction of immunoregulatory mechanisms and anergy. (B) Viral infections and exposure to TLR agonists at initiation of co-stimulation blockade abrogate the induction of tolerance. Alloreactive T cells are protected against early deletion, becoming activated and mediating the rejection of skin allografts. (C) Viruses but not TLR agonists abrogate the induction of tolerance when given after initial deletion of alloreactive T cells. We postulate that low-affinity alloreactive T cells survive early cell death and become activated by viral infection, possibly by a cross-reactive mechanism.
Acute Viral Infections
Acute infection of C57BL/6 with LCMV simultaneously with theinitiation of co-stimulation blockade completely abrogated theinduction of tolerance and resulted in the rapid rejection ofallogeneic tissues (Figure 4B).105–107 The viral infectionactivated alloreactive T cells, stimulating the proliferationof these cells with a corresponding increase in cell number.108The use of co-stimulation blockade to induce tolerance to alloantigenswas also unsuccessful in mice that were persistently infectedwith LCMV.104 These results suggest that the success of co-stimulationblockade is extremely susceptible to inflammatory conditionsthat are present during the initial phase of tolerance induction.The negative effects of a viral infection at this early timepoint of tolerance induction were mimicked by exposure to TLRagonists (Figure 4B).107,109 Coadministration of agonists toTLR2, TLR3, TLR4, or TLR9 with co-stimulation blockade rescuedalloreactive T cells from cell death and resulted in the rejectionof transplanted tissues.107 Together, these findings indicatethat activation of the innate immune system during the earlieststages of co-stimulation blockade will bypass the requirementof CD40L:CD40 signaling in the antigen-mediated activation ofT cells and result in rejection of transplanted tissues.
The death of alloreactive T cells occurs rapidly after the initiationof co-stimulation blockade, with a significant proportion ofcells being deleted within 24 h.107 Despite this massive lossof alloreactive T cells, acute infection of mice with eitherLCMV or PV within 1 to 15 d after engraftment disrupted theinduction of tolerance and resulted in the rejection of skinallografts (Figure 4C).103,105 Selective depletion of CD8+ cellsfrom LCMV-infected mice significantly delayed allograft rejection,revealing an important role for CD8 T cells in the virus-inducedrejection.103 We postulate that T cells that recognize alloantigenswith low affinity are not efficiently deleted by co-stimulationblockade and that these surviving cells are then activated bythe viral infection, possibly through cross-reactive mechanisms(Figure 4C). In contrast to infection with LCMV or PV, injectionof the TLR3 agonist poly(I:C) at the time of engraftment didnot result in the rejection of skin allografts, suggesting thatonce the alloreactive T cell repertoire has been reduced bycell death, activation of the innate immune response is notsufficient to abrogate tolerance in the absence of viral antigens.103
Memory Alloreactive T Cells Generated by Viral Infection
In humans, the pretransplantation frequency of memory phenotypealloreactive T cells, as determined by IFN- enzyme-linked immunosorbentspot assay, correlates with the risk for development of an acuterejection episode after transplantation.54 The results describedpreviously indicate that memory alloreactive T cells are generatedby previous viral infections, but the ability of these memoryT cells to respond against a subsequent exposure to alloantigensand to mediate rejection is an unresolved issue. In vitro experimentshave indicated that memory CD8 T cells generated by viral infectionswill proliferate in vitro when cultured with allogeneic cellsand that at least a proportion of these responding T cells arevirus specific, further supporting a role for cross-reactivity.24,57,60Studies by our group have shown that GP33-specific memory CD8T cells derived from LCMV-immune mice proliferate in vitro whenstimulated with H2d cell lines.24 Both CMV- and EBV-specificCD8 T cells from human PBMC proliferate after in vitro stimulationwith irradiated HLA-mismatched lymphocytes.57,60 These studiesindicate that under optimal conditions in vitro, alloantigensstimulate the division of virus-specific memory CD8 T cell andsuggest that the cross-reactive memory T cells will respondagainst foreign tissues in vivo. We have observed that LCMV-specificmemory CD8 T cells participate in the immune response againstskin allografts in vivo (M.A.B. et al., unpublished data, 2006).In these experiments, splenocytes from LCMV-immune C57BL/6 micewere labeled with CFSE and transferred into congenic hosts thatsubsequently received a skin allograft. In mice that were engraftedwith allogeneic skin, virus-specific CD8 T cells were foundto proliferate and to increase in number. Together, these experimentssuggest that memory alloreactive T cells generated by previousinfections actively respond to alloantigens and represent along-lived barrier to the transplantation of foreign tissues.
Memory alloreactive CD8 T cells that are laid down after a viralinfection present a specific impediment for the induction oftolerance by co-stimulation blockade. Memory T cells are lessdependent on co-stimulatory signals to generate functional recallresponses, and memory alloreactive T cells produced by previousexposure to alloantigens are refractory to the induction oftolerance by co-stimulation blockade.25,110–113 Memoryalloreactive T cells generated by a single infection with LCMVare also resistant to co-stimulation blockade and will rapidlyreject skin allografts.24 Moreover, mice infected sequentiallywith heterologous viruses have increased frequencies of alloreactivememory T cells and show an enhanced resistance to tolerance-inducingprotocols.24,25 These findings demonstrate that memory T cellsgenerated by previous viral infections will present a significantobstacle for the use of co-stimulation blockade to induce toleranceto allografts in patients who have been exposed to pathogensthroughout their lifetime.
The immune system has evolved such that multiple diverse antigen-specificmemory TCR repertoires accumulate over a lifetime. Memory Tcells that are specific to previously encountered pathogensbut that also cross-react with a newly encountered pathogenare preferentially maintained or expanded, such that the T cellrepertoire specific to the previous pathogen becomes permanentlyaltered. These activated cross-reactive memory T cells playa role in heterologous immunity by modulating the T cell immunehierarchy and the private specificity of individual antigen-specificTCR repertoires, leading to an alteration in the balance betweenprotective immunity and immunopathology. Virus-specific T cellresponses that are cross-reactive with alloantigens can alsoalter the memory allospecific T cell pool and influence graftrejection and tolerance induction. Thus, getting a certain infectionin a host with a particular MHC and at the wrong time in a sequenceof other infections might have significant detrimental consequencesfor the host. To understand the fine role that memory T cellscan play in balancing the induction of protective immunity versuspathology, we need to learn more about the consequences of heterologousimmunity and cross-reactive T cell responses.
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17 response, the amino acid motif IRSS is common,28 and in the allospecific H2-Kd–restricted HLA-CW3 Vb10 response in DBA/2 mice, SxG in the first three positions of the CDR3 region is a common motif.29 These similarities between individuals in V
, IFN-
, and macrophage inflammatory protein 1
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Abstract
ALTERATIONS OF IMMUNE T...
