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

Alexandra Tsitsiklis,Elina I Zuniga,Shaodong Dai,Kristina M Geiger,Derek J Bangs,Andrew J Modzelewski,Ellen A Robey,Yang Wang,Lara Labarta-Bajo,Shiao W Chan,Lydia K Lutes

doi:10.3389/fimmu.2020.01464

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 Ld-restricted CD8+ T cell response directed against a peptide derived from the parasite antigen GRA6. The MHC-1 Ld molecule has limited peptide binding compared to conventional MHC molecules such as Kb or Db, which correlates with polymorphisms associated with “elite control” of HIV in humans. To investigate the link between the unusual MHC-1 molecule Ld and the generation of “elite controller” CD8+ T cell responses, we compared the GRA6-Ld specific T cell response to the well-studied OVA-Kb specific response, and demonstrated that GRA6-Ld 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 Ld that results in broader peptide binding. We investigated the effect of this Ld W97R mutation on another robust Ld-restricted response against the IE1 peptide during Murine Cytomegalovirus (MCMV) infection. This mutation leads to an increase in exhaustion markers in the IE1-Ld specific CD8+ T cell response. Our results indicate that limited peptide binding by MHC-1 Ld correlates with the development of robust and protective CD8+ T cell responses that may avoid exhaustion during chronic infection.

Highlights

Individuals differ dramatically in their ability to mount CD8+ T cell responses against intracellular infections, as exemplified by Human Immunodeficiency Virus (HIV) infected individuals who can control the virus without anti-retroviral therapy [1]
Our results indicate that limited peptide binding by major histocompatibility complex (MHC) correlates with the development of CD8+ T cell responses that resist exhaustion, and are consistent with a model in which limited peptide binding by MHC-1 and the corresponding low self-reactivity of CD8+ T cells favor protective responses during chronic infections
While MHC-1 molecules with limited peptide binding are associated with HIV control in humans and T. gondii control in mice, the link between the peptide binding characteristics of MHC and effective CD8+ T cell responses has not been experimentally examined

Summary

Introduction

Individuals differ dramatically in their ability to mount CD8+ T cell responses against intracellular infections, as exemplified by Human Immunodeficiency Virus (HIV) infected individuals who can control the virus without anti-retroviral therapy [1]. While the ability of elite control-associated alleles, such as Human Leukocyte Antigen (HLA)-B57 and B27, to induce strong CD8+ responses undoubtedly depends on their ability to bind particular viral peptides, these MHC alleles are associated with autoimmunity and resistance to other infections, suggesting that more general properties of these molecules may underlie their ability to generate potent CD8+ T cell responses [3,4,5]. A CD5low CD4+ T cell clone displayed resistance to activation-induced cell death and superior expansion during secondary challenge [13]. This suggests that high vs low selfreactivity T cells may be designed to fulfill distinct roles in different infection settings. The role of CD8+ T cells with low self-reactivity remains unknown

Methods

Results

Conclusion