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 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.

T cell self-reactivity during thymic development dictates the timing of positive selection

“…As the organism ages, however, it may become advantageous to have a more diverse, specialized T cell repertoire, particularly to fight chronic infections. In line with this notion, we recently reported that TG6 T cells are resistant to exhaustion and provide a protective response to T. gondii chronic infection, properties that are linked to limited binding of self-peptides to the restricting MHC-I molecule L d (Blanchard et al 2008;Chu et al 2016;Tsitsiklis et al 2020).…”

Novel Vβ specific germline contacts shape an elite controller T cell response

“…B27 and B57) with limited ability to bind peptides 7,8 . Restricted peptide binding by mouse H2-L d is correlated with resistance to CD8 T cell exhaustion during chronic infection 9 , and is controlled by amino acid polymorphisms that also correlate strongly with HIV control 7,10 . The paradoxical association between restricted peptide binding and elite control may be due to the combination of weak binding to self-peptides coupled with strong binding to particular antigenic peptides 8, 9 . However, precisely why certain MHC-I molecules favor the development of particularly potent CD8 T cell responses remain a mystery.…”