T cell-mediated anti-tumor immunity is thought to be achieved by a multistep process called the cancer-immunity cycle
[1]. It includes the following seven steps: (1) release of cancer antigens, (2) cancer antigen presentation, (3) priming and activation, (4) trafficking of T cells to tumors, (5) infiltration of T cells into tumors, (6) recognition of cancer cells by T cells, and (7) killing of cancer cells. Thus, the cycle is initiated by the uptake of tumor antigens, including tumor-associated antigens and neoantigens, by DCs, the professional antigen-presenting cells. Tumor antigen-captured DCs then migrate into the draining lymph nodes where recirculating naïve T cells and memory T cells scan antigenic peptides presented by DCs in association with class I and class II major histocompatibility complex (MHC) molecules (
Figure 1). The CCL19/CCL21-CCR7 axis is known to play a pivotal role in the migratory activities of DCs and recirculating T cells
[1][15]. While immature DCs in peripheral tissues dominantly express CCR6, the surface expression of CCR7 is upregulated upon antigen-loading and DC maturation
[1][15]. Since CCL21 is abundantly produced by lymphatic vessels, CCR7-expressing DCs initiate trans-lymphatic migration and home into T cell areas of the draining lymph nodes where matured DCs start producing CCL19 (
Figure 1)
[3][16][17]. The lymph nodes also have unique vascular structures called high endothelial venules (HEVs), which produce CCL21 and function as the gateways for recirculating naïve T cells and memory T cells that commonly express CCR7 (
Figure 1)
[18][19]. In addition, although CCL19 is not produced by HEVs, it is displayed on the luminal surfaces of HEVs by transcytosis
[20]. After homing into the lymph nodes, naïve T cells and memory T cells further migrate toward CCL19-producing mature DCs localized in the T cell areas
[1][15]. Upon encounter with cognate antigenic peptides presented by mature DCs, antigen-specific naïve T cells proliferate and differentiate into various effector T cell subsets in accordance with the local cytokine milieu, whereas memory T cells start rapid expansions for recall immune responses
[21]. Furthermore, conventional DCs have two subtypes known as type 1 (cDC1s) and type 2 (cDC2s)
[22]. It is now known that cDC1s preferentially induce the differentiation of naïve CD4
+ T cells and CD8
+ T cells into Th1 cells and CTLs, respectively
[3][16][17], whereas cDC2s preferentially induce the differentiation of naïve CD4
+ T cells into Th2 cells and Th17 cells (
Figure 1)
[3][16][17]. Importantly, cDC1s selectively express XCR1 and are the most efficient DCs in the cross-presentation of exogenous antigens to CD8
+ T cells
[22]. Of note, while cDC1s activate CCR7-expressing naïve CD8
+ T cells
[22], activated CD8
+ T cells in turn produce XCL1, the ligand of XCR1 (
Figure 1)
[22]. This further promotes the interactions of CD8
+ T cells and cDC1s, leading to full differentiation of effector CTLs
[22]. In secondary immune responses, mature DCs also produce CCL3, CCL4, CCL5, CCL17, CCL22, CXCL9, CXCL10, and CXCL11
[22]. Since Th1 cells express CCR5 and CXCR3, while Th2 cells, Th17 cells, and Treg cells express CCR4
[22], these chemokine–chemokine receptor axes contribute to the rapid expansion of effector T cells (
Figure 1).