Loss of HLA-DO function impairs the development of memory CD4 T cells

Abstract

Abstract DO is an accessory protein that binds DM for trafficking to MIIC and has peptide editing functions. DO is mainly expressed in thymic medulla and B cells. Using biochemical experiments, our lab has discovered that DO has differential effects on editing peptides of different sequences. DO increases binding of DM-resistant peptides, and reduces the binding of DM-sensitive peptides to the HLA-DR1 molecules. In a separate line of work, we have established that reduced densities of antigen presentation by B cells during the contraction phase of an infection, induces quiescence in antigen experienced CD4 T cells as they differentiate into memory T cells. This quiescent phenotype helps memory CD4 T cell survival and promotes effective memory responses to secondary Ag challenge. Based on our mechanistic understanding of DO function, it would be expected that in immunized DO-KO mice, presentation of altered densities of pMHC by B cells would lead to faulty development of memory CD4 T cells. We tracked the development of DR1 restricted H5N1 flu specific memory CD4 T cells and B cells post flu vaccine immunization in DR1+/DO-KO mice and found that immunized DR1+/DO-KO mice had fewer CD4 memory T cells and memory B cells than DR1+/DO-WT mice. By in vitroand in vivorecall experiments, we found that memory responses elicited in DR1+/DO-KO mice were compromised. Using a second model antigen, OVA, we confirmed our findings, i.e., altered memory development and secondary responses in DO-KO mice. These results demonstrate that in the absence of DO, the presentation of cognate foreign antigens in the DO-KO mice is altered and can hamper the proper development of memory cells. These findings suggest a justification for the late appearance of DO in warm blooded mammals. R37 AI060040 R01 AI121174 R01 AI130210