T Cell Trafficking

Author : Daniel T. Fisher
Publisher :
ISBN 13 :
Total Pages : 179 pages
Book Rating : 4.:/5 (764 download)

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Download or read book Selective Targeting of Microvascular Gateways for T Cell Trafficking by Interleukin-6 written by Daniel T. Fisher and published by . This book was released on 2011 with total page 179 pages. Available in PDF, EPUB and Kindle. Book excerpt: A successful adaptive immune response against invading pathogens or tumor progression depends on the rapid expansion of effector T cell populations and their subsequent delivery to sites of infection or disease. T cell activation requires efficient interactions between antigen-loaded dendritic cells (DCs) and rare cognate na© ve T cells. Thus, effective control of fast-multiplying pathogens relies on efficient screening of antigen-bearing DCs by na© ve T cells that traffic through high endothelial venules (HEVs), the major portals for entry of blood-borne lymphocytes into lymph nodes (LNs). To effectively kill their targets, effector lymphocytes must leave the LNs and efficiently traffic to peripheral sites of infection or tumor progression. Under acute inflammatory conditions the display of adhesion molecules and chemokines expressed on the microvasculature that support lymphocyte trafficking can be rapidly altered.^Therefore, we examined if cues provided by both local and systemic inflammation could increase na© ve T cell trafficking to lymphoid organs. Experiments using systemic thermal therapy (STT) to examine the effects of febrile temperatures on lymphocyte trafficking found increased intravascular display of two gatekeeper homing molecules, intercellular adhesion molecule-1 (ICAM-1) and CCL21 chemokine in HEVs in lymphoid tissues, but not in normal extralymphoid vessels. Moreover, local immunization with mature DCs increased the intravascular display of peripheral lymph node addressin (PNAd) and ICAM-1 on HEVs of draining LN, but not contralateral LNs. In both of these models of acute inflammation, increased trafficking molecule expression on HEVs resulted in improved entry of na© ve and central memory T cells. Induction of PNAd and ICAM-1, but not CCL21, was mediated by signaling through interleukin-6 (IL-6).^Following activation in the LN, effector T cells need to efficiently traffic to sites of infection or tumor progression to kill their cellular targets. Our studies demonstrate that homeostatic trafficking of tumor-reactive cytotoxic CD8 T lymphocytes across tumor microvessels is limited, providing a potential immune escape mechanism. However, real-time intravital imaging revealed acute inflammatory signals triggered by STT increased vascular expression of ICAM-1, changing the adhesive function of tumor vessels to support trafficking of effector CD8 T cells. As in the case of acute inflammatory responses in HEVs, induction of ICAM-1 and CD8 T cell trafficking in tumor vessels was mediated by IL-6. Improved IL-6 dependent trafficking of effector CD8 T cells was causally linked to apoptosis of cognate tumor targets.^Taken together, these studies reveal a highly regulated lymphocyte-endothelial-IL-6 biological axis that modulates the immune response by directing lymphocyte trafficking to specific tissue sites.