88 Chemotaxis and chemorepulsion Ulixertinib in the context of T-cell trafficking have been studied in the process of thymic emigration. Egress of mature thymocytes from the medulla to the periphery has been shown to be orchestrated by chemoattraction exerted by S1P and a simultaneous fugetactic function of CXCL12, which induces cells to leave the thymus.81,89 A bimodal effect of chemokines on memory T-cell trafficking has also been demonstrated in cancer. Certain growing tumours initially generate the chemokine CXCL12 at a level that induces T-cell chemoattraction, but ultimately

establish an immune-privileged site through the chemorepellent effect of high levels of CXCL12 on tumour-specific T cells. In this setting, T-cell chemorepulsion impairs cytotoxic T lymphocyte-mediated lysis of tumour cells, which requires that the effector makes direct contact

with the target cell.90 Fugetaxis and chemorepulsion may coexist in situations where the concentration of the chemokine drives cells from chemotaxis to fugetaxis, but dual receptor engagement may take place. In fact, it has been shown that the chemokine CXCL12 mediates a concentration-dependent chemorepulsive effect on diabetogenic T cells by altering firm adhesion. As this effect is G-protein-coupled receptor dependent but is only partially reversed by CXCR4 blockade, it has been suggested that alternative downstream CXCL12 signalling pathways mediated by protein coupled receptor 1 (RDC1)/CXCR7 Navitoclax cost may trigger chemorepulsion.91 Memory plasma cells reside on CXCL12-expressing stromal cells of bone marrow and rest there for a long periods.92–94 Until recently, evidence demonstrating the existence of survival niches for memory CD4 T cells has been elusive.95,96 In immune reactions characterized by long-term antigen persistence (virus or adjuvants), memory-phenotype

CD4 T cells are found in the spleen and lymph nodes for long periods.97,98 In contrast, following immunization in the presence of soluble adjuvants (lipopolysaccharide PR-171 solubility dmso or monophosphoryl lipid A), memory CD4 T cells in the spleen or lymph nodes substantially decrease in number 1 week after immunization.99,100 These T cells have been shown to locate to the bone marrow and rest on IL-7-expressing stromal cells of the bone marrow.99 The relocation of antigen-experienced CD4 T cells to the bone marrow is dependent on integrin α2β1, a collagen receptor. Inhibition of integrin α2β1 on primed CD4 T cells results in defective relocation of antigen-specific CD4 T cells to the bone marrow and reduced B-cell help (e.g. reduced affinity maturation). It is still unknown how the memory T cells migrate to their survival niches in the bone marrow, although they express CCR2 and CXCR6.99 The bone marrow is presumably the most best tissue for long-term localization of CD4 T cells primed by blood-borne antigen.