Abstract
Kinetic and biophysical parameters of T cell receptor (TCR) and peptide:MHC (pMHC) interaction define intrinsic factors required for T cell activation and differentiation. Although receptor ligand kinetics are somewhat cumbersome to assess experimentally, TCR:pMHC affinity has been shown to predict peripheral T cell functionality and potential for forming memory. Multimeric forms of pMHC monomers have often been used to provide an indirect readout of higher affinity T cells due to their availability and ease of use while allowing simultaneous definition of other functional and phenotypic characteristics. However, multimeric pMHC reagents have introduced a bias that underestimates the lower affinity components contained in the highly diverse TCR repertoires of all polyclonal T cell responses. Advances in the identification of lower affinity cells have led to the examination of these cells and their contribution to the immune response. In this review, we discuss the identification of high- vs. low-affinity T cells as well as their attributed signaling and functional differences. Lastly, mechanisms are discussed that maintain a diverse range of low- and high-affinity T cells.
Highlights
The T cell immune response is composed of diverse sets of T cell receptors with a normally distributed range of affinities for pMHC [1, 2]
Current hypotheses suggest the highest affinity T cells have a competitive advantage during the immune response, based on the assumption that they would receive stronger and more prolonged activation signals than T cells with lower affinity interactions [5,6,7]
Affinity is defined as the probability of a receptor (TCR)–ligand interaction and is one of the most commonly used measurements to predict the T cell response to antigen
Summary
The T cell immune response is composed of diverse sets of T cell receptors with a normally distributed range of affinities for pMHC [1, 2]. Current hypotheses suggest the highest affinity T cells have a competitive advantage during the immune response, based on the assumption that they would receive stronger and more prolonged activation signals than T cells with lower affinity interactions [5,6,7]. Evidence is emerging to suggest the lack of skewing toward the highest affinity T cell repertoire, instead of proposing a distribution of affinities and maintenance of diversity throughout the immune response [8, 9]. This T cell diversity has been shown to be important for homeostasis of the immune system, but the process of maintaining affinity diversity is unclear. We further discuss factors that support and favor the survival of lower affinity T cells and, highlight the important contribution of low-affinity T cells and a broad affinity distribution in the immune response
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