Investigation of Potential Sex Bias in Lymphocyte Trafficking in Response to Fever-Range Thermal Stress
Tisdale, Arwen A.
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The immune response has the capability of responding to foreign invaders and sensing changes in the body’s own cells. This process is termed immune surveillance and relies upon the continuous recirculation of lymphocytes through secondary lymphoid organs, particularly lymph nodes. Naïve lymphocytes must travel through the circulation and enter the lymph nodes across specialized high endothelial venules (HEVs), wherein they encounter antigen-presenting dendritic cells positioned adjacent to these unique cuboidal “gatekeeper” HEVs. This provides the opportunity for productive encounters with T cells expressing cognate T cell receptors. These specialized cuboidal venules support the efficient extravasation of lymphocytes into secondary lymphoid tissues (lymph nodes, Peyer’s Patches) where they can mount an appropriate response. Improvement of immune surveillance as a therapeutic avenue of research is of much interest. We have identified thermal stress as a means of increasing this surveillance trafficking checkpoint in the T lymphocyte response. This stress, heating mice to 39.5°C ± 5°C for 6 hours, termed whole body hyperthermia (WBH) can be used to increase the trafficking of T lymphocytes into lymphoid tissues to mount an appropriate immune response. Whether there are any differences in response to fever-range WBH and/or baseline trafficking between the sexes is the focus of this paper. Trafficking was evaluated in male and female C57BL/6 mice treated with fever-range thermal stress for 6 hours and compared to control mice, which were not exposed to heat. We found that male and female mice differ in their maintenance of core body temperature during treatment, indicating that males are less tolerant to temperature deviations under febrile conditions. Specifically, males undergo many more “out of target” temperature readings (temperatures above 40°C) as compared to their female counterparts. In spite of these sex differences in response to temperature sensing, trafficking responses to fever-range thermal stress were similar in both sexes. Thermal induction of the expression of endothelial trafficking molecule intracellular adhesion molecule-1 (ICAM-1) on the HEV occurred to the same extent in both male and female mice. Moreover, increased ICAM-1 expression resulted in enhanced trafficking of lymphocytes across HEV located in peripheral lymph nodes. We observed no difference in thermally-induced trafficking between male and female mice. We conclude that while the mechanisms controlling thermally-induced lymphocyte trafficking are conserved in both sexes, the ability to withstand thermal stress exhibits a sex bias through mechanisms that remain to be determined.