Abstract
T cell receptor–major histocompatibility complex (TCR–MHC) affinities span a wide range in a polyclonal T cell response, yet it is undefined how affinity shapes long-term properties of CD8 T cells during chronic infection with persistent antigen. Here, we investigate how the affinity of the TCR–MHC interaction shapes the phenotype of memory CD8 T cells in the chronically Toxoplasma gondii-infected brain. We employed CD8 T cells from three lines of transnuclear (TN) mice that harbor in their endogenous loci different T cell receptors specific for the same Toxoplasma antigenic epitope ROP7. The three TN CD8 T cell clones span a wide range of affinities to MHCI–ROP7. These three CD8 T cell clones have a distinct and fixed hierarchy in terms of effector function in response to the antigen measured as proliferation capacity, trafficking, T cell maintenance, and memory formation. In particular, the T cell clone of lowest affinity does not home to the brain. The two higher affinity T cell clones show differences in establishing resident-like memory populations (CD103+) in the brain with the higher affinity clone persisting longer in the host during chronic infection. Transcriptional profiling of naïve and activated ROP7-specific CD8 T cells revealed that Klf2 encoding a transcription factor that is known to be a negative marker for T cell trafficking is upregulated in the activated lowest affinity ROP7 clone. Our data thus suggest that TCR–MHC affinity dictates memory CD8 T cell fate at the site of infection.
Highlights
CD8 T cells are a cornerstone of the adaptive immune defense to intracellular pathogens with their capacity to operate as antigen-experienced effector and memory cells
We refer to these CD8 T cell clones as R7-I, R7-II, and R7-III CD8 T cells [24]
We previously showed these CD8 T cell clones to differ in their T cell receptor (TCR) 3D affinity to cognate ROP7 peptide, with R7-I being the strongest binder at 4 μM and R7-II the weakest at 109 μM
Summary
CD8 T cells are a cornerstone of the adaptive immune defense to intracellular pathogens with their capacity to operate as antigen-experienced effector and memory cells. Pathogen-specific CD8 effector T cells rapidly expand and differentiate during the acute infection, followed by a phase of contraction and development of long-lived memory T cells [1, 2]. Most of our understanding of T cell responses to chronic infections is derived from models where pathogen control is incomplete. The interaction of the T cell receptor (TCR) with the pathogen antigenic epitope loaded on the major histocompatibility complex (MHC) is essential in maintaining effective CD8 T cell control of persistent intracellular pathogens. Efforts have been made to elicit the effect of TCR–MHC affinity on the fate of the resulting T cells, often this relied on varying the antigenic peptide rather the TCR [2, 6]. The simple question of how T cells of different affinity to a given antigen fare during chronic infection remains unresolved
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