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

Nat Commun. 2016 Dec 15;7:13848. doi: 10.1038/ncomms13848.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adjuvants, Immunologic
  • Adoptive Transfer
  • Animals
  • Antigens / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Freund's Adjuvant
  • Green Fluorescent Proteins / genetics
  • Mice
  • Mice, Knockout
  • Mycobacterium tuberculosis / immunology
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Pertussis Toxin / immunology
  • Precursor Cells, T-Lymphoid / immunology*
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Spleen / cytology
  • Up-Regulation


  • Adjuvants, Immunologic
  • Antigens
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Antigen, T-Cell, alpha-beta
  • Green Fluorescent Proteins
  • Freund's Adjuvant
  • Pertussis Toxin