Investigating a role for HLA-DO in the development of CD4 memory cells

Abstract

Abstract HLA-DO (DO) is a MHC class II-encoded protein in humans (known as H2-O in mice). It is expressed only in thymic medulla, B cells and some subsets of dendritic cells. Although DO is found to form a stable complex with HLA—DM, its biological functions remain poorly understood. Based on biochemical experiments, our lab has previously proposed a model suggesting that DO enhances binding of DM-resistant peptides, and reduces the binding of DM-sensitive peptides to the HLA-DR1 molecules in vitro. We also have established that a reduced density of antigen presentation by B cells during the contraction phase of an infection, induces of anergy in CD4 memory T cells, a condition that helps memory CD4 T cell survival and effective memory response to a second challenge. Based on our model, it would be expected that in immunized DO-KO mice, presentation of altered densities of DM-resistant pMHC by B cells would fail to induce long-lived, multifunctional memory CD4 T cells. We tracked the development of DR1 restricted flu specific CD4 memory T cells three months post flu vaccine immunization in DR1+/DO-KO mice. We found that the DR1+/DO-KO mice had fewer flu specific CD4 memory T cells than DR1+/DO-WT mice. By in vitro and in vivo recall experiments, we also found that the secondary immunological responses in DR1+/DO-KO mice were compromised. In addition, we recovered fewer memory B cells from immunized DR1+/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 potentially hamper the proper development of memory cells after the resolution of the infection. These findings support the idea that the expression of DO might ensure the proper development of memory cells.