Analysis of the effects of fever-range whole body hyperthermia on lymphocyte trafficking and retention within lymph nodes
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An effective immune response requires tight orchestration of diverse factors responsible for controlling the recirculation of lymphocytes along the secondary lymphoid organs. In this context, lymph nodes (LN) are the central hubs, strategically positioned throughout the body where the core players in immunity congregate. As reservoirs of the immunogenic content of tissue sites, LN are in a unique position to bring T cells into contact with dendritic cells (DC) bearing cognate antigen. Therefore, active trafficking of T cells and careful survey for the DCs in the LN are critical determinants in the development of successful immunity. Previous studies from our lab have shown that trafficking of blood-borne naïve T cell into LNs is augmented by elevated temperatures in the febrile range following administration of fever-range whole body hyperthermia (WBH). While these findings have shed light on the immunoprotective mechanism of action of fever, it remains an open question whether fever-range thermal stress alters the retention of lymphocytes and their dwell times within the LN. This question was addressed in the current study by investigating the effects of febrile temperatures in modulating the rate of T cell egress from the LN. When mice with T cells pre-seeded in the LN were treated with fever-range WBH we observed a marked increase in retention of naïve CD4+ and CD8+ T cell subsets. This activity appeared to act via regulation of T cell function since lymphocytes needed to be exposed to heat in vivo in order for retention to be augmented during WBH. Increased retention in response to fever-range WBH was also detected in experiments employing direct lymphatic injection of T cells into the LN, to eliminate any potential effects of thermally-induced trafficking into LN. Further, in vitro chemotaxis studies showed that thermally treated T cells were more responsive to the chemokine CCL21, which plays a critical role in guiding T cell motility in LN, whereas chemotactic responses to another chemokine, CXCL12, were not affected by heat treatment. Together, our studies establish that the thermal component of fever enhances the retention of T cells in LN, which is predicted to increase the probability that T cells will successfully encounter their cognate antigen, thereby facilitating the development of a more efficient primary adaptive immune response.