Hemoglobin alpha regulates T-lymphocyte activation and mitochondrial function

Abstract

We have recently discovered hemoglobin alpha a1 (Hb-a1 mRNA and Hb protein) in T-lymphocytes and previously reported that its expression was sensitive to mitochondrial redox perturbations. However, outside of its occurrence and basic characterization, the functional role of Hb in T-lymphocytes remained unknown. Herein, we identify Hb in both CD4+ and CD8+ T-lymphocyte subsets, and found its expression is highly dynamic, differs between the two subtypes, and is dependent upon activation stage. Further, the loss of Hb by use of a novel T-lymphocyte-specific Hb knock-out mouse impairs mitochondrial function, dysregulates cytokine production, and lowers the activation threshold primarily in CD4+ T-lymphocytes, indicating a critical role for Hb within this subset. While these data suggested the loss of Hb in T-lymphocytes may promote aberrant activation of autoreactive T-lymphocytes, surprisingly, we discovered that mice lacking Hb in T-lymphocytes exhibited reduced severity of experimental autoimmune encephalomyelitis (EAE) compared to wild-type control animals. Interestingly, T-lymphocytes lacking Hb in vivo appeared to function identically to wild-type controls, which did not explain the protection against EAE. In contrast, T-lymphocyte Hb knock-out mice displayed significantly reduced levels of circulating immunoglobulins and CD40L expression compared to their wild-type counterparts during EAE, suggesting possible impaired intercellular communication. These data elucidate a previously unrecognized role for Hb in T-lymphocyte function, which may have implications for hemoglobin-related diseases (i.e., hemoglobinopathies).