Memory of mice and men: CD8⁺ T‐cell cross‐reactivity and heterologous immunity

Abstract

The main functions of memory T cells are to provide protection upon re-exposure to a pathogen and to prevent the re-emergence of low-grade persistent pathogens. Memory T cells achieve these functions through their high frequency and elevated activation state, which lead to rapid responses upon antigenic challenge. The significance and characteristics of memory CD8+ T cells in viral infections have been studied extensively. In many of these studies of T-cell memory, experimental viral immunologists go to great lengths to assure that their animal colonies are free of endogenous pathogens in order to design reproducible experiments. These experimental results are then thought to provide the basis for our understanding of human immune responses to viruses. Although these findings can be enlightening, humans are not immunologically naïve, and they often have memory T-cell populations that can cross-react with and respond to a new infectious agent or cross-react with allo-antigens and influence the success of tissue transplantation. These cross-reactive T cells can become activated and modulate the immune response and outcome of subsequent heterologous infections, a phenomenon we have termed heterologous immunity. These large memory populations are also accommodated into a finite immune system, requiring that the host makes room for each new population of memory cell. It appears that memory cells are part of a continually evolving interactive network, where with each new infection there is an alteration in the frequencies, distributions, and activities of memory cells generated in response to previous infections and allo-antigens.

Central Memory CD8+ T Cells Induce Graft-versus-Host Disease and Mediate Graft-versus-Leukemia

“…Regardless of their precise activation history, the T CM used in our studies clearly responded against both allogeneic MHC-peptide and syngeneic-MHC-miHA peptide complexes. Such cross-reactivity, or heterologous immunity, has been well demonstrated in T cells reactive against both allogeneic MHC (47-62) and against viral peptides on a shared MHC (61,(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73), analogous to our results in the B63 BALB/c and C3H.SW3 B6 models, respectively. Alloreactive memory cells are thought to be barriers to successful solid organ transplantation (48, 51-53, 55, 74), and the present data that T CM mediate both GVHD and GVL are consistent with these studies.…”

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

“…It has been proposed that cross-reactivity may explain why T cell responses to some epitopes in human viral infections have a narrow oligoclonal TCR repertoire while others are diverse (86). It is intriguing to speculate that TV9 may be a cross-reactive determinant that HIV-1 shares with a heterologous organism(s) (87).…”

Vaccination and heterologous immunity: educating the immune system

“…40,47 Clear networks of crossreactive epitopes and patterns of beneficial or detrimental heterologous immunity have been defined in specific virus sequences in mouse models (Supplementary Figure 1). [24][25][26][27][28][29][30][31][32][33][34][48][49][50][51][52][53] For example, in the C57BL/6 mouse (H2 b ), CD8 T cell crossreactive epitopes have been defined between LCMV and Pichinde virus (PICV), LCMV and vaccinia virus (VACV), LCMV and murine cytomegalovirus (MCMV), LCMV and IAV, IAV and MCMV, and PICV and VACV, and complex networks of mouse or human T cell crossreactivity can exist between two viruses. 23,24,27,28,34,[54][55][56] Furthermore, structural studies on crossreactivity between LCMV and VACV epitopes can pinpoint the target of crossreactivity and render the OVA SIINFEKL epitope crossreactive with LCMV by an amino acid substitution.…”