An Unusual MHC Molecule Generates Protective CD8+ T Cell Responses to Chronic Infection

Abstract

The CD8+ T cell response to the intracellular parasite Toxoplasma gondii varies dramatically between mouse strains, resulting in stark differences in control of the parasite. Protection in BALB/c mice can be attributed to an unusually strong and protective MHC-1 L d-restricted CD8+ T cell response directed against a peptide derived from the parasite antigen GRA6. The MHC-1 L d molecule has limited peptide binding compared to conventional MHC molecules such as K b or D b , which correlates with polymorphisms associated with "elite control" of HIV in humans. To investigate the link between the unusual MHC-1 molecule L d and the generation of "elite controller" CD8+ T cell responses, we compared the GRA6-L d specific T cell response to the well-studied OVA-K b specific response, and demonstrated that GRA6-L d specific T cells are significantly more protective and resistant to exhaustion in chronic T. gondii infection. To further investigate the connection between limited peptide presentation and robust T cell responses, we used CRISPR/Cas9 to generate mice with a point mutation (W97R) in the peptide-binding groove of L d that results in broader peptide binding. We investigated the effect of this L d W97R mutation on another robust L d-restricted response against the IE1 peptide during Murine Cytomegalovirus (MCMV) infection. This mutation leads to an increase in exhaustion markers in the IE1-L d specific CD8+ T cell response. Our results indicate that limited peptide binding by MHC-1 L d correlates with the development of robust and protective CD8+ T cell responses that may avoid exhaustion during chronic infection.

Chronic infection control relies on T cells with lower foreign antigen binding strength generated by N-nucleotide diversity

“…In line with this result, following infection with C. neoformans, CD4 + T cells with low self-pMHC reactivity, and thus presumably with lower foreign reactivity PLOS BIOLOGY [34], predominated among the responding effector T cells during the chronic infection phase. These experimental findings expand on previous work suggesting that, during chronic infection, T cells with lower pMHC-reactivity predominate in both CD4 + [37] and CD8 + T cells [38,39].…”

“…During chronic infection, the antigen-specific T cells of lower pMHC reactivities predominate, whereas T cells of greater pMHC reactivity predominate during an acute infection. Our experimental data from CD4 + T cells corroborated this result and are consistent with evidence from other experimental studies of both antigen-specific CD4 + and CD8 + T cells indicating that T cells with lower pMHC reactivity predominate during chronic infection [37][38][39].…”

CXCR3 regulates stem and proliferative CD8+ T cells during chronic infection by promoting interactions with DCs in splenic bridging channels

“…Although cDC-2s are equipped to promote T effector differentiation, they also have high levels of PD-L1, suggesting that they may have differential effects on the fate of stem and proliferative populations, depending on the specific setting. We have shown previously that GRA6-specific CD8+ T cells are resistant to exhaustion and do not express PD-1, partially because of unusually low reactivity to self-peptide-MHC complexes (Tsitsiklis et al, 2020;Lutes et al, 2021). Thus, GRA6-specific cells are Cell Reports 38, 110266, January 18, 2022 13…”

“…We have previously described a highly protective, immunodominant CD8+ T cell response mounted against a peptide derived from the parasite protein GRA6 presented by the major histocompatibility complex (MHC) class I molecule H-2L d (Blanchard et al, 2008;Feliu et al, 2013;Chu et al, 2016;Salvioni et al, 2019;Tsitsiklis et al, 2020). During chronic infection in H-2L d -expressing mice, GRA6-specific CD8+ T cells experience continuous antigen stimulation in the spleen and exhibit ongoing proliferation and differentiation.…”

“…However, unlike the LCMV chronic infection model, in which T cells express the inhibitor receptor PD-1 and exhibit functional exhaustion, T cells in the T. gondii infection model retain potent effector function and lack expression of inhibitory receptors. As a result, proliferative intermediate cells are only robustly produced following PD-1 blockade in the LCMV infection model, whereas T MEM , T INT , and T EFF cell populations are produced spontaneously and continuously in T. gondii-infected mice (Chu et al, 2016;Tsitsiklis et al, 2020). These features make T. gondii infection a valuable model to investigate differentiation of stem, intermediate, and T EFF cells in the setting of chronic infection.…”