Oral administration of antigen mainly induces T helper lineage-negative CD200+ CTLA4+ anergic CD4+ T cells which tend to become regulatory T cells

Abstract

Abstract CD4+ T cells do not normally undergo productive immune responses to orally administered foreign antigens. It has been proposed that this oral tolerance phenomenon is explained by CD4+ T cells with T cell receptors (TCRs) specific for MHCII-bound peptides from ingested antigens becoming unresponsive (anergic) or differentiating into T regulatory (Treg) cells. Not much is known, however, about the phenotype and function of cells undergoing this process within the polyclonal CD4+ T cell repertoire. We addressed this issue by using I-Ab tetramers containing a foreign peptide called 2W to track 2W:I-Ab-specific CD4+ T cells after oral gavage of C57BL/6 mice with 2W peptide. These CD4+ T cells underwent weak clonal expansion when exposed orally to 2W peptide and generated a population consisting of 10% Foxp3+ Treg cells, 10% CXCR5+ follicular helper cells (Tfh), and ~3 % TBET+ Th1 or RORgt+ Th17 cells. The dominant subpopulation, however, did not express any of the known T helper cell lineage markers. Analysis of 80 surface proteins including CD73, FR4, CD200, PD-1, P2X7, and CTLA-4 revealed that these T helper lineage-negative (Thlin−) cells were more similar to anergic cells than to effector or Treg cells. In addition, adoptive transfer of sorted 2W:I-Ab-specific Thlin− cells followed by oral gavage of the peptide showed that these Foxp3− cells can become Foxp3+ Treg cells much more efficiently than naïve T cells. Collectively, our data demonstrate that the majority of CD4+ T cells exposed to oral antigen become Foxp3− anergic cells with a tendency to become Treg cells.