Investigating sex differences in the mitochondria of CD4+ and CD8+ T lymphocytes

Abstract

Sex differences in immunity have been observed in many contexts including infectious diseases, cancer, and autoimmunity. Females generally mount stronger innate and adaptive responses, and as a result tend to have lower rates of infectious disease and non-reproductive cancers, but are more prone to inflammatory and autoimmune diseases. These sex differences in the immune system and immune response can be caused by genetic and hormonal factors. In light of increasing evidence that mitochondria are sexually dimorphic in their structure and function, a growing area of interest is the role mitochondria might play in the observed sex differences in immunity. Mitochondrial morphology can dictate the metabolic phenotype of the cell, and in turn this can modulate cellular responses to immunological activation. Determination of how these mitochondrial properties differ across the sexes could therefore provide insight into the mechanisms that drive sex differences in immunity. Using confocal microscopy we found that CD8+ T cells isolated from murine liver showed the greatest sexual dimorphism in mitochondrial morphology, with females exhibiting a greater mitochondrial count than males and a more branched mitochondrial network, while cells isolated from the spleen and lymph nodes did not show significant sex differences. Flow cytometry revealed that there were no sex differences in mitochondrial mass or polarisation ex vivo, but that an in vivo immune challenge might have the potential to decrease these paraments. We further demonstrated that CD69 expression by CD4+ and CD8+ T cells isolated from both spleen and lymph node was upregulated to a greater extent in females than males following in vivo immune challenge. Finally, proteomic analysis of CD4+ and CD8+ T cells revealed sex differences in the expression of a number of mitochondrial proteins including components of the ATP synthase enzyme, and mitochondrial fission and fusion proteins such as Fis1 and Opa1. The results of this project therefore provide preliminary evidence suggesting males and females differ in their mitochondrial content, and this is therefore an area that warrants further investigation.