The process of lymphocyte trafficking across blood vessel walls represents a critical checkpoint in the development of a fine-tuned adaptive immune response. The major focus of our laboratory has been to define the molecular mechanisms that control the trafficking patterns of lymphocytes throughout the body, with an aim toward developing novel therapeutic strategies to enhance the effectiveness of cancer immunotherapy. To this end, we have investigated the thermal element of fever as a model of acute inflammation. These studies revealed that fever-range thermal stress (38-40°C) has a profound influence on the delivery of blood-borne lymphocytes to lymphoid organs that are the powerhouse of the immune system. The thermal response was found to be unexpectedly integrated, invoking independent activities in lymphocytes and in vascular endothelium. Moreover, we have shown that multiple trafficking molecules (L-selectin, α4β7 integrin, CCL21, ICAM-1) are targeted by febrile temperatures to heighten immune surveillance of peripheral lymphoid organs.

Recent studies by our group have identified a novel role for the proinflammatory cytokine, interleukin-6 (IL-6), in mediating thermal effects on lymphocyte homing. We have shown that this process involves a trans-signaling mechanism in which the gp130 signal transduction molecule is dually engaged by IL-6 and a soluble form of the IL-6 receptor. This signaling nexus targets discrete events in the multistep adhesion cascade that governs lymphocyte entry into tissues. Collectively, the picture to emerge is that the thermal element of fever acts as a rheostat to mobilize trafficking of lymphocytes to physiologically relevant sites. Understanding of the dynamics of lymphocyte trafficking during acute inflammation has provided clues regarding impediments to lymphocyte entry across vascular gateways in the tumor microenvironment. We are presently exploring new avenues to modify the adhesive landscape of tumor vessels in order to improve the access of cytolytic effector T cells to tumor cell targets in situ.