Direct Visualization of Cross-Reactive Effector and Memory Allo-Specific CD8 T Cells Generated in Response to Viral Infections

Abstract

CD8 T cell cross-reactivity between heterologous viruses has been shown to provide protective immunity, induce immunopathology, influence the immunodominance of epitope-specific T cell responses, and shape the overall memory population. Virus infections also induce cross-reactive allo-specific CTL responses. In this study, we quantified the allo-specific CD8 T cells elicited by infection of C57BL/6 (B6) mice with lymphocytic choriomeningitis virus (LCMV). Cross-reactive LCMV-specific CD8 T cells were directly visualized using LCMV peptide-charged MHC tetramers to costain T cells that were stimulated to produce intracellular IFN-γ in response to allogeneic target cells. The cross-reactivity between T cells specific for LCMV and allogeneic Ags was broad-based, in that it involved multiple LCMV-derived peptides, but there were distinctive patterns of reactivity against allogeneic cells with different haplotypes. Experiments indicated that this cross-reactivity was not due to the expression of two TCR per cell, and that the patterns of allo-reactivity changed during sequential infection with heterologous viruses. The allo-specific CD8 T cells generated by LCMV infection were maintained at relatively high frequencies in the memory pool, indicating that memory allo-specific CD8 T cell populations can arise as a consequence of viral infections. Mice previously infected with LCMV and harboring allo-specific memory T cells were refractory to the induction of tolerance to allogeneic skin grafts.

Patients, Pathogens, and Protective Immunity: The Relevance of Virus-Induced Alloreactivity in Transplantation

“…In B6 mice, serial exposure to acute viral infections leads to progressive accumulation of alloreactive memory T cells. When a critical threshold of memory cells is reached either by serial infection or by adoptive transfer of donor-specific memory cells, a potent barrier to tolerance induction is observed (7,35). This is in accordance with work from Welsh's and Heeger's groups showing that primed/memory T cells resist CD154 blockade-induced tolerance (36,37).…”

“…Since then, broad-based cross-reactivity has been described in more detail in LCMV-immune B6 (H-2 b ) mice; four unique LCMV epitopes that were stained by tetramer were found to have a subset of alloresponsive T cells against either H-2 d or H-2 k (35). Furthermore, through the use of ␣-chain ϩ/Ϫ mice that are incapable of secondary ␣-chain rearrangement, the authors found that dual TCR expression couldn't account for their observations (35).…”

Prevention of Allograft Tolerance by Bacterial Infection with Listeria monocytogenes

“…Previous studies demonstrating the ability of lymphocytic choriomeningitis virus and Pichinde virus, but not murine cytomegalovirus and vaccinia, viral infections to prevent the induction of tolerance (7,11,12) have led to the suggestion that the acquired Fig. 1 (untreated, n ϭ 3; anti-CD154 (␣-CD154)/DST, n ϭ 6; anti-CD154/DST plus LM, n ϭ 10); p Ͻ 0.01 for MyD88 Ϫ/Ϫ vs MyD88 Ϫ/Ϫ plus anti-CD154 (␣-CD154)/DST plus LM and vs MyD88 Ϫ/Ϫ plus anti-CD154/DST; p Ͻ 0.01 for MyD88 plus anti-CD154/DST vs MyD88 Ϫ/Ϫ plus anti-CD154/DST plus LM.…”

“…Experimental animal models have revealed that the exposure of hosts to viral or parasitic agents prior to transplantation can result in the development of memory T cells (5)(6)(7) that are resistant to the effects of anti-CD154 therapy (8,9). A subset of these pathogen-specific memory T cells has been shown to cross-react, by molecular mimicry, with alloantigen presented by donor or recipient MHC molecules (10).…”

“…In addition to viral infections prior to transplantation, acute or persistent viral infections at the time of transplantation can prevent the induction of tolerance by costimulation-targeting regimens (11)(12)(13)(14). This is thought to occur via direct activation of cross-reacting alloreactive T cells by viral Ags (7,9) or upon bystander activation of allospecific T cells (9,12). We and others have also shown that engagement of single TLRs, receptors that recognize molecular patterns expressed by viruses, fungi, parasites, and bacteria, is sufficient to prevent transplantation tolerance by anti-CD154 mAb (15)(16)(17).…”