CD8 T Cell Cross-Reactivity Networks Mediate Heterologous Immunity in Human EBV and Murine Vaccinia Virus Infections

Abstract

Here we demonstrate complex networks of CD8 T-cell cross-reactivities between influenza A virus (IAV) and Epstein- Barr virus (EBV) in humans and between lymphocytic choriomeningitis virus (LCMV) and vaccinia virus (VV) in mice. We also show directly that cross-reactive T-cells mediate protective heterologous immunity in mice. Subsets of T-cell populations reactive with one epitope cross-reacted with either of several other epitopes encoded by the same or the heterologous virus. Human T-cells specific to EBV-encoded BMLF1280-288 could be cross-reactive with two IAV or two other EBV epitopes. Mouse T-cells specific to the VV-encoded a11r198-205 could be cross-reactive with three different LCMV, one Pichinde virus, or one other VV epitope. Patterns of cross-reactivity differed among individuals, reflecting the private specificities of the host’s immune repertoire, and divergence in the abilities of T-cell populations to mediate protective immunity. Defining such cross-reactive networks between commonly encountered human pathogens may facilitate the design of vaccines.

Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44highCD62LlowCD8+TEMCells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpesvirus Infection

“…In HSV-seropositive humans, the memory CD8 ϩ T cells mature during childhood after exposure to other viruses and other pathogens, and the T-cell repertoire that develops cross-reacts with different viruses, including members of the same (or different) herpesvirus family (62)(63)(64)(65). However, this is unlikely for the three VP13/14 epitopes identified in this study because (i) the sequences of the VP13/14 286 -294 , VP13/14 504 -512 , and VP13/14 544 -552 epitopes are highly conserved between HSV-1 strains (100%) and HSV-2 strains (88%) (see Table S1 in the supplemental material); (ii) no significant homology exists between the amino acid sequences of these three epitopes and the VP13/14 amino acid sequences of varicella-zoster virus (VZV; 44% to 55%) and cytomegalovirus (CMV; 44% to 55%) strains (Table S1); (iii) the sequence alignments with published sequences of VP13/14 proteins from other human herpesviruses (e.g., VZV and CMV) did not reveal significant homol-ogies that might be translated to functional cross-reactive T cells (Table S1); and (iv) the three HLA-A*02:01-restricted VP13/14 epitopes reported here to be recognized by CD8 ϩ T cells from HLA-A*02:01-positive, HSV-1-seropositive individuals are also recognized with the same magnitude and breadth by CD8 ϩ T cells developed in laboratory HLA-A*02:01 Tg mice that are selectively bred in sanitized environments and infected with HSV-1.…”

Vaccination and heterologous immunity: educating the immune system

“…27,28 These responses were activated and proliferated during severe infections like acute infectious mononucleosis (IM) or influenza A infection. Unique EBV/IAV crossreactive populations have been identified in different HLA-A2+ patient populations, suggesting that crossreactive patterns may be predicted during human infections (Supplementary Figure 2).…”

“…LCMV and VACV share a complex matrix of CD8 T cell crossreactivity, which has been defined and studied molecularly. 28,52,57 Herein, adoptive transfer studies showed that T cell private specificity of crossreactive memory responses plays a major role in the protection and immunopathology. 32,33 The IAV+LCMV respiratory infection mouse model is noteworthy in that there are both higher titers of LCMV and much greater lung pathology in mice previously infected with IAV, both detrimental effects of heterologous immunity.…”

“…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.…”

“…The mechanisms of heterologous immunity can vary, but the focus of this review is on experimental systems where both beneficial and detrimental heterologous immunity are mediated by crossreactive T cells. 22,23 More than 20 years of research have delineated basic principles of heterologous immunity, such as (1) T cell crossreactivity is quite common between unrelated pathogens and alters T cell immunodominance; 24 (2) networks of crossreactive T cells alter the efficacy of the T cell response and influence protective immunity and immunopathology; [25][26][27][28][29][30] (3) T cell crossreactivity can lead to narrowing of the T cell repertoire and generation of viral escape mutants; 31 (4) the private specificity of crossreactive T cells can determine an individual's disease outcome in regards to protective immunity and immunopathology; [31][32][33] (5) heterologous immunity can reduce the effectiveness of vaccines due to immunodominant skewing of undesired T cell responses; 29,34 (6) peptide-dependent interventions or cytokine Transactions of the Royal Society of Tropical Medicine and Hygiene blocking therapy can be used to prevent severe pathology caused by heterologous immunity; 25,30,34 and (7) the immune response to each new pathogen impacts the frequencies, distributions and activities of memory T cells to previous infections. 22,35,36 The contention is that heterologous immunity is the norm, not the exception, but given the diversity in human genetics, MHC and infection histories, is it too complicated an issue to address?…”