key: cord-0752938-ugk8wov9
authors: Selin, Liisa K; Welsh, Raymond M
title: Plasticity of T Cell Memory Responses to Viruses
date: 2004-01-22
journal: Immunity
DOI: 10.1016/s1074-7613(03)00356-x
sha: 80fc59d028bb4f3a66f03b6fa124ac80bef70978
doc_id: 752938
cord_uid: ugk8wov9

Virus-specific memory T cell populations demonstrate plasticity in antigenic and functional phenotype, in recognition of antigen, and in their ability to accommodate new memory T cell populations. The adaptability of complex antigen-specific T cell repertoires allows the host to respond to a diverse array of pathogens and accommodate memory pools to many pathogens in a finite immune system. This is in part accounted for by crossreactive memory T cells, which can be employed in immune responses and mediate protective immunity or life-threatening immunopathology.

. In the LCMV system, some (e.g., NP396) specific T cells, which are (CCR7 ϩ , CD62L ϩ [first and third models]) or early differentiated (CD45 Ϫ , CD27 ϩ , CD28 ϩ [second model]) pheno-probably most highly stimulated by antigen, are completely eliminated from the host. However, T cells with types appear to be more resistant to apoptosis and cycle more rapidly, and, upon antigen exposure, are other specificities (e.g., GP33) undergo various states of anergy in which there is a loss in cytolytic ability, IL-2, better at producing IL-2 and proliferating when compared to the effector (CCR7 Ϫ , CD62L Ϫ [first and third TNF␣, and then IFN␥ production, in that order ( an advantage in both antiviral and antitumor responses where antigenic variants can be quite common.

Despite heterogeneity in TCR usage, many epitope-Diversity of Antigen-Specific specific responses have in the CDR3 region distinct Memory TCR Repertoires amino acid motifs that are maintained between clono-Antigen-specific TCR repertoires are highly diverse. The types and between different individuals. For example, adaptive immune response needs to recognize a large in the human HLA-A2-restricted influenza A M1-58 V␤17 number of foreign antigens and has evolved to generate response, the amino acid motif IRSS is common (Naua diverse ␣␤ TCR response by . Thus, the TCRs on the antigen-specific T cell of high-frequency clonotypes and a large number of clones are unique to the individual, and these unique low-frequency clonotypes, which could be described by regions have been referred to as the "private specificity" a power law-like distribution (Naumov et al., 2003 ; Pewe for that epitope-specific response. This variation is et al., 1999). This means that a small number of clones probably a consequence of the random stochastic prowere present at high frequencies and ever-increasing cess of TCR rearrangement in the thymus, which results numbers of clones were present at lower and lower in variations in the naive peripheral TCR repertoire, and frequencies. Furthermore, when the structure of the M1of the random stochastic process whereby a T cell enspecific repertoire was analyzed by focusing on many counters an APC presenting its cognate ligand (Bousso different subsets of the repertoire, such as clonotypes et al., 1998). T cell clones that are stimulated early may using J␤2.7 or those whose CDR3 region encodes the dominate the response by interfering with the stimulaamino acid sequence IRSS, the clonotype frequencies

is degenerate in the number of antigens it can recognize. to that of the larger whole repertoire. The power law-It has been calculated, on the basis of positional analysis like distribution and the self similarity, which described of various amino acid substitutions at different residues this influenza A M1-58-specific response, suggested of a peptide, that a given TCR has the potential to recogthat this repertoire was organized in the form of a fractal nize a million different peptide-MHC combinations (Masystem. Fractal systems occur throughout nature, in son, 1998). Reports of CD8 T cells recognizing epitopes such common forms as snowflakes, trees, and blood encoded by apparently unrelated viruses are increasing. vessels, where there is a self similarity of structure. We The colored dots represent T cell populations that have different specificities. The intracellular IFN␥ staining for epitope-specific responses during particular viral infections are also depicted. A naive immune system is challenged with either of two heterologous viruses, LCMV or PV, and generates a T cell response to the immunodominant epitopes. These acute responses then decline but maintain the same hierarchy of immunodominant responses in the memory state. If an immune system that has been conditioned with one virus is exposed to the other heterologous virus, T cell populations that are crossreactive with the two viruses (red outlined) will expand preferentially, dominate the response, and go onto memory.

Plasticity of Immunodominance Hierarchies. The mobilization of crossreactive memory cells into a primary an allogeneic target have shown that different regions of the same TCR can bind to two different targets (Daniel immune response can alter the immunodominance of subsequent T cell responses. In genetically identical et al., 1998; Speir et al., 1998) . This type of crossreactivity would be difficult to predict. However, a crossreac-animals with a naive immune system, the hierarchy of T cells specific to immunodominant epitopes is consis-tion involving the same determinants on the TCR would be easier to predict and identify by searching databases tent and predictable (Brehm et al., 2002). However, studies in humans have shown that there is variability in the for peptide sequences with similar amino acids accessible to the TCR; this "molecular mimicry" method was hierarchies of T cells responding to different HLA-A2restricted HIV epitopes in individual patients (Betts et used to identify some of the crossreactive epitopes identified above (Mason, 1998 

ologous immunity can therefore be complicated and duction was caused by crossreactivity or by a nonselecdifficult to predict, although they are quite reproducible tive cytokine-dependent activation, but the IFN␥ conin experimental models.

We suggest that heterologous immunity may underlie was a selective expansion LCMV-specific T cells with variabilities in pathology observed in some human viral some but not other epitope specificities, consistent with infections. It is noteworthy that many viruses, including a crossreactive antigen-driven expansion ( 

in the young adult might lead to recruitment of cross-memory phenotype, but, as a consequence of crossreactivity, viral infections leave mice with much higher reactive T cells and altered disease pathology. 

vere eosinophilia (Walzl et al., 2000) . Thus, memory Adams et al., 2003) .

T cells specific to heterologous agents may affect the Heterologous Immunity and Autoimmunity. Reactiva-Th1 or Th2 bias on subsequent exposure to allergens tion of crossreactive memory T cells may play a role or new infections. in mediating autoimmune diseases, such as multiple sclerosis, diabetes mellitus, Crohn's disease, or rheu- loss in memory to previously encountered antigens When a TMEV variant was engineered to encode a pep- (Selin et al., 1996 (Selin et al., , 1999 Smith et al., 2002) . Thus, the tide containing the encephalitogenic myelin proteolipid apparent need for antigen persistence to maintain longprotein (PLP139-151) epitope, mice infected with this term memory in humans may have more to do with virus developed a rapid onset paralytic demyelinating restimulating memory populations reduced after other disease. Furthermore, mice infected with TMEV encodinfections than with an absolute need of memory cells to ing a variant peptide, which shared only 6 of 13 amino receive an antigenic stimulus to survive. Several recent acids with PLP139-151, also displayed rapid-onset dispublications have stressed the long-term stability of ease and developed Th1-type CD4 T cells crossreactive CD8 T cells specific to nonpersistent human viruses with PLP139-151. but there still is greater than a 10-fold loss with time Heterologous Immunity and Immune Deviation. Reac- (Hammarlund et al., 2003) .

Part of the plasticity of the memory CD8 T cell recontributing to immune deviation. If a memory pool is sponse is its volatility in the wake of infections. 2002) . A pertinent question is pressed a Th2-type response and the associated eosinophilia in the lung when exposed to an allergen (Erb whether these events are interrelated or distinct. 

A separate observation possibly related to the above mentioned lymphopenia is the finding that viral infec-CD8 T cell loss can be as high as 80% after inoculation of mice with poly I:C. The memory T cell loss is by tions cause a permanent loss in memory to previously encountered viruses. This was initially shown by limiting apoptosis, as the residual T cells react with annexin V and stain with markers for caspase activation. dilution assays in mice infected with LCMV, PV, VV, and MCMV in sequence (Selin et al., 1996) et al., 2003) . These high frequencies mean that the capacity of a host to to HSV are more profound in hosts treated with low doses of cyclophosphamide (Pfizenmaier et al., 1977) . accommodate T cells specific to a wide variety of pathogens is limited, instead of being a proverbial bottomless The relationship between these events remains unclear, but it has recently been shown that the virus-induced pit. Here, the immune system demonstrates plasticity by deleting some memory T cells in order to accommo-lymphopenia is more dramatic in young than in old mice, and young mice tend to generate a stronger T cell re-date others. One can envision two models to account for the long-sponse to a virus than old mice (Jiang et al., 2003b) .

Bona Fide Memory Cells versus Homeostatically Di-term reduction in memory CD8 T cells specific to previous pathogens after a host encounters a second patho-viding Cells with a Memory Phenotype. The recovery of bona fide memory CD8 T cells from their lymphopenia-gen. A passive, or competition model, would predict that there are a finite number of survival niches for memory associated loss would be dependent on their ability to compete with the antigen-specific T cells responding to cells in the lymphoid organs, and the large numbers of newly arising CD44hi CD8 T cells simply compete with the ongoing infection and with T cells homeostatically expanding to fill the lymphopenic environment. Interest-the previously residing cells for these niches. An active model would predict that there is a mechanism that ingly, lymphopenic environments induce the homeostatic proliferation of CD8 T cells, which expand in num-selectively kills off the preexisting memory cells.

LCMV infection in mice have indicated that the memory cells, once depleted, fail to recover and remain depleted signals from IL-7 and IL-15, represent another example of the plasticity in functional phenotypes of memory in long-term memory (Kim and Welsh, 2004) . This argues on behalf of the active model, though it certainly seems T cell populations (Tan et al., 2002; Goldrath et al., 2002) . Not all of these cells proliferate comparably, and it is that under some conditions competition between the old and new memory cells must be a factor. thought that those undergoing the greatest degree of homeostatic division may be self reactive with host anti-

The depleted populations of virus-specific memory gens. The net effect is that there are considerable numbers of these CD44hi CD8 "pseudomemory" cells that T cells stay at reduced frequencies after resolution of infection but then remain stable thereafter, unless the have not gone through the differentiation scheme of bona fide memory cells.

host receives another infection (Selin et al., 1996 (Selin et al., , 1999 

The colored dots represent T cell populations that have different specificities. The intracellular IFN␥ staining for epitope-specific responses during particular viral infections are also depicted. The immunodominant hierarchy of antigen-specific responses is established during the peak of the CD8 T cell response to virus and remains the same during the silencing phase into memory for both LCMV and PV infection. After a heterologous virus infection, such as PV challenge of an LCMV-immune host, the LCMV-specific hierarchy is modified, the crossreactiveepitope responses (NP205) are preserved and expanded in response to PV infection, and the noncrossreactive epitope responses are reduced in number. In an LCMV-immune host, the PV-specific immunodominant hierarchy is different from that of a naive host, with the crossreactive epitope response (NP205) being immunodominant.

permanently changed by subsequent infections with putatively unrelated viruses. Significantly, these continu-tently infected with LCMV as adults and mounting a low-grade antiviral T cell response led to a substantial ously evolving memory T cell responses participate in and influence disease outcome of each new infection, deletion of the PV-specific T cells, in comparison to control or LCMV-immune recipients (S.K. Kim and whether it be harmful or beneficial to the host. R.M.W., submitted). Thus, persistent infections may enact a severe and continuous toll on preexisting memory

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