CD4+ T cells display increased cross reactivity when primed with peptides of lower affinity for MHC (BA8P.165)

Abstract

Abstract Studies propose the degree of T cell cross reactivity for peptide antigens is associated with similarities in the amino acid residues contacting TCR. Here we advance this concept by assessing how the stability of peptide for MHC contributes to cross reactivity in demyelinating autoimmune disease by evaluating two CNS antigens MOG35-55 (myelin oligodendrocyte glycoprotein) and NFM15-35 (neurofilament medium protein). These peptides share identical TCR contact residues yet vary at 3 MHC anchors such that MOG exhibits greater stability than NFM for I-Ab. This difference dictates encephalitogenic potential as well because MOG promotes demyelination and NFM does not. Polyclonal CD4+ T cells primed with MOG or NFM were probed for affinity and cross reactivity using MHC monomers presenting the priming peptides or the encephalitogenic peptides MOG(42P) and MOG(47A), which vary from wild type MOG at TCR contact residues. The 2D micropipette adhesion frequency assay used to assess these parameters showed that NFM and MOG expanded splenic CD4+ T cells that recognized 47A and 42P with similar frequencies and low affinities ~1.8 x10-6 μm4. Interestingly though, NFM specific cells had a greater capacity to recognize multiple peptides than MOG specific cells and this potential was unique to individual clones. Thus, peptide stability for MHC influences the degree of cross reactivity in peripheral tissues and provides a unique point of comparison for studying cross reactivity in the CNS.