The MHC Class I Antigen Processing Components TAP and ERAAP Sculpt the MHC Class II-restricted Self Peptidome and Modulate the CD4+ T Cell Receptor Repertoire Impacting T Helper Responses to Microbial Pathogens. (106.24)

Abstract Humans deficient in TAP or ERAAP function present with recurrent infections despite elevated CD4+ T cell numbers. As CD4+ T cells regualte multiple immune response, their actions are critical to anti-microbial responses. Recently, studies have identified a role for TAP and ERAAP in generating influenza, Listeria and minor histocompatibility antigen peptides recognized by CD4+ T cells. Though the MHC class I-restricted self peptidome is known to be regulated by TAP and ERAAP, the affect on MHC class II-restricted self peptidome is unknown. Here we show that the MHC class II-restricted self peptidome is dramatically altered by the activities of TAP and ERAAP. The CD4+ T cell repertoire correspondingly had profound alterations in the diversity of the TCR CDR3 region that defines antigen specificity. This altered CD4+ T cell repertoire led to altered class II-restricted peptide recognition pattern in TAP-deficient mice. Though some peptides were recognized at an enhanced magnitude, the recognition of others was either lost or newly acquired. Taken together these data suggest that TAP and ERAAP sculpt class II-restricted peptidomes and thereby affect the CD4+ T cell repertoire. The recognition of a new, yet overlapping, immunome by TAP deficient CD4+ T cells demands further investigation to understand the extent of interaction between the MHC class I and class II antigen processing pathways and their effects on anti-microbial responses particularly in TAP deficient individuals.