T Lymphocyte–Endothelial Interactions: Emerging Understanding of Trafficking and Antigen-Specific Immunity

Abstract

Antigen-specific immunity requires regulated trafficking of T cells in and out of diverse tissues in order to orchestrate lymphocyte development, immune surveillance, responses, and memory. The endothelium serves as a unique barrier, as well as a sentinel, between the blood and the tissues, and as such it plays an essential locally tuned role in regulating T cell migration and information exchange. While it is well established that chemoattractants and adhesion molecules are major determinants of T cell trafficking, emerging studies have now enumerated a large number of molecular players as well as a range of discrete cellular remodeling activities (e.g., transmigratory cups and invadosome-like protrusions) that participate in directed migration and pathfinding by T cells. In addition to providing trafficking cues, intimate cell–cell interaction between lymphocytes and endothelial cells provide instruction to T cells that influence their activation and differentiation states. Perhaps the most intriguing and underappreciated of these “sentinel” roles is the ability of the endothelium to act as a non-hematopoietic “semiprofessional” antigen-presenting cell. Close contacts between circulating T cells and antigen-presenting endothelium may play unique non-redundant roles in shaping adaptive immune responses within the periphery. A better understanding of the mechanisms directing T cell trafficking and the antigen-presenting role of the endothelium may not only increase our knowledge of the adaptive immune response but also empower the utility of emerging immunomodulatory therapeutics.

Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation

“…Cell adhesion molecules such as ICAM-1/2 and VCAM-1 are enriched in caveolae and support transcellular migration by engaging infiltrating cell podocytes (Abadier et al, 2015; Carman and Martinelli, 2015; Millan et al, 2006). Th17 cells rely primarily on an αLβ2/ICAM-1 interaction (Rothhammer et al, 2011; Stromnes et al, 2008), whereas Th1 cells employ an α4/VCAM-1 complex for migration (Glatigny et al, 2011).…”

“…Both expression of Cav1 (Shin et al, 2005; Wu et al, 2016) and the density of endocytotic vesicles in CNS endothelium increase during acute MS and EAE (Brown, 1978; Claudio and Brosnan, 1992). Endothelial caveolae may provide a migratory route for myelin-specific T cells into the CNS (Raine et al, 1990), due to clustering of adhesion molecules (Carman and Martinelli, 2015; Millan et al, 2006). Caveolar activity also enhances leukocyte migration across the meninges (Santizo et al, 2002).…”

The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment

“…BECs constitutively express both MHC class I and MHC class II molecules and upregulate these in response to inflammatory signals (78). They possess antigen-processing machinery and have been shown to take up and present antigens in vivo and in vitro (209). Critical costimulatory molecules CD80 and CD86 are not expressed on cultured human endothelial cells, rendering them unable to stimulate naïve CD8 + T cells (210).…”

“…However, limited activation of memory CD8 + T cells that have less stringent costimulatory requirements has been observed (210). Co-inhibitory molecules including PD-L1 and PD-L2 can be expressed by endothelial cells (209, 211). Expression of these immune checkpoint molecules is upregulated by TNFα and can inhibit CD8 + T cell activation (211).…”

T Cell Trafficking through Lymphatic Vessels

“…While it is well established that adhesion molecules and their integrin ligands play an important role in T cell entry into LNs through HEVs (100), not much is known about their role in T cell egress across lymphatic sinuses. A role for leukocyte function-associated antigen 1 (LFA-1) in delaying egress of T cells across lymphatic sinuses has recently been suggested.…”