Molecular mechanisms of CD8(+) T cell trafficking and localization

Abstract

Cytotoxic CD8(+) T cells are potent mediators of host protection against disease due to their ability to directly kill cells infected with intracellular pathogens and produce inflammatory cytokines at the site of infection. To fully achieve this objective, naïve CD8(+) T cells must be able to survey the entire body for the presence of foreign or "non-self" antigen that is delivered to draining lymph nodes following infection or tissue injury. Once activated, CD8(+) T cells undergo many rounds of cell division, acquire effector functions, and are no longer restricted to the circulation and lymphoid compartments like their naïve counterparts, but rather are drawn to inflamed tissues to combat infection. As CD8(+) T cells transition from naïve to effector to memory populations, this is accompanied by dynamic changes in the expression of adhesion molecules and chemokine receptors that ultimately dictate their localization in vivo. Thus, an understanding of the molecular mechanisms regulating CD8(+) T cell trafficking and localization is critical for vaccine design, control of infectious diseases, treatment of autoimmune disorders, and cancer immunotherapy.

Fig. 1

Extravasation of naïve CD8⁺ T cells across high endothelial venules. The initial interaction between a naïve CD8⁺ T cells and HEVs occurs when L-selectin (CD62L) on the T cell binds to peripheral node addressins (PNAd) on the endothelium. The subsequent rolling that occurs due to these interactions allows the chemokine CCL21 to stimulated CCR7-mediated firm adhesion of LFA-1 to ICAM on the HEV. The naïve CD8⁺ T cell will then scan the HEV before finally transmigrating through the endothelium and entering the lymph node

Fig. 2

Examples of 6-sulfo-sialyl-Lewis X motifs on different glycans. a Symbolic representation of monosaccharides found in O- and N-linked glycans. b Symbolic representation of the 6-sulfo-sialyl-Lewis X carbohydrate motif. c Core 1 O-glycans, d core 2 O-glycans, and e N-glycans can all bear 6-sulfo-sialyl-Lewis X. This carbohydrate motif on sialomucins such as CD34 serves as the ligand for CD62L. Expression of 6-sulfo-sialyl-Lewis X on core 1 O-glycans (as shown in c) is also used to define HEVs in vivo by reacting with the MECA-79 antibody

Fig. 3

Memory CD8⁺ T cells express P- and E-selectin ligands in response to inflammation. Most memory CD8⁺ T cells do not express core 2 O-glycans or bind to P- or E-selectin during homeostatic, steady-state conditions (left). However, in response to inflammatory IL-15, memory CD8⁺ T cells will synthesize core 2 O-glycans in a TCR-independent manner. The newly synthesized core 2 O-glycans on proteins such as PSGL-1 serve as ligands for P- and E-selectin and will subsequently attract these memory CD8⁺ T cells to inflamed tissues

Fig. 4

Differentiation of tissue-resident memory CD8⁺ T cells. Following infection, naïve CD8⁺ T cells become activated in draining lymph nodes by antigen, co-stimulation, and inflammatory cytokines, which drive their conversion into effector CD8⁺ T cells. These activated CD8⁺ T cells will then enter the efferent lymph and return to the circulation via the thoracic duct. After homing into tissues, effector CD8⁺ T cells will subsequently differentiate into resident memory CD8⁺ T cells in response to TGF-β. IL-33 and TNFα may also contribute to the establishment of tissue-resident memory CD8⁺ T cell populations