Low-affinity CD4+T cells are major responders in the primary immune response

• Type of Material: Article
• Authors: Ryan J. Martinez, Emory University; Rakieb Andargachew, Emory University; Hunter A. Martinez, Emory University; Brian Evavold, Emory University
• Language: English
• Date: 2016-12-15
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2016 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms13848
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 7
• Start Page: 13848
• End Page: 13848
• Grant/Funding Information: This work was supported by NIH grant T32 AI007610, RO1 AI096879, RO1 AI110113, R01 NS071518 and F31 NS086130.
• Keywords: MEMORY CELLS; Science & Technology - Other Topics; REPERTOIRE DIVERSITY; TCR AFFINITY; IN-VIVO; PEPTIDE-MHC; CROSS-REACTIVITY; Science & Technology; Multidisciplinary Sciences; CD4(+) T-CELLS; CD8 CORECEPTOR; RECEPTOR AFFINITY; PRECURSOR FREQUENCY
• Research Categories: Health Sciences, Immunology; Biology, Microbiology

Abstract

A robust primary immune response has been correlated with the precursor number of antigen-specific T cells, as identified using peptide MHCII tetramers. However, these tetramers identify only the highest-affinity T cells. Here we show the entire CD4+ T-cell repertoire, inclusive of low-affinity T cells missed by tetramers, using a T-cell receptor (TCR) signalling reporter and micropipette assay to quantify naive precursors and expanded populations. In vivo limiting dilution assays reveal hundreds more precursor T cells than previously thought, with higher-affinity tetramer-positive T cells, comprising only 5-30% of the total antigen-specific naive repertoire. Lower-affinity T cells maintain their predominance as the primary immune response progresses, with no enhancement of survival of T cells with high-affinity TCRs. These findings demonstrate that affinity for antigen does not control CD4+ T-cell entry into the primary immune response, as a diverse range in affinity is maintained from precursor through peak of T-cell expansion.