Title: Chemokines and their receptors in t cell migration
Abstract: The discovery of the chemokines and their receptors has dramatically changed our understanding of leukocyte traffic in immune defence and disease. In the past 15 years about 50 human chemokines and nearly 20 receptors have been identified and characterised. Early on, chemokines were considered as mediators of inflammation, but with time more and more chemokines were found that function mainly in the basal traffic of leukocytes, lymphocytes in particular. Inflammatory chemokines are expressed in inflamed tissues by resident and infiltrating cells on stimulation with proinflammatory cytokines or microbial products. They are mainly responsible for the recruitment of effector cells including granulocytes, monocytes and effector T cells. In contrast, the homing or homeostatic chemokines are constitutively produced in discrete areas within lymphoid and non-lymphoid tissues. They are involved in maintaining the physiological traffic and positioning of cells largely belonging to adoptive immune system. A very impressive development in the past couple of years was the recognition that T lymphocytes can express most chemokine receptors, but that the expression is strictly regulated and dependent on the state of maturation, priming, activation and differentiation. It has also been shown that chemokine receptors can be used as markers of distinct T cell subsets. In addition, the progress in the chemokine research has opened new perspectives for therapeutic intervention of leukocyte recruitment during inflammatory diseases based on the inhibition of chemokine receptors. I will comment on main contributions to this progress from our laboratory. Loetscher P, Seitz M, Clark-Lewis I, Baggiolini M, Moser B. Monocyte chemotactic proteins MCP-1, MCP-2, and MCP-3 are major attractants for human CD4+ and CD8+ T lymphocytes. FASEB J 1994: 8 : 1055–1060. In the early nineties, the importance of chemokines for lymphocytes was in doubt. This report demonstrates that the monocyte chemotactic proteins, MCP-1, MCP-2, MCP-3 which were regarded as selective for monocytes at that time, are potent attractants for T lymphocytes. Loetscher P, Seitz M, Clark-Lewis I, Baggiolini M, Moser B. Activation of NK cells by CC chemokines: chemotaxis, Ca2+ mobilization and enzyme release. J Immunol 1996: 156 : 322–327. This paper shows that the monocyte chemotactic proteins, MCP-1, MCP-2, MCP-3 also activate NK cells. They induce chemotactic migration, calcium mobilization and enzyme release. Loetscher P, Seitz M, Baggiolini M, Moser B. Interleukin-2 regulates CC chemokine receptor expression and chemotactic responsiveness in T lymphocytes. J Exp Med 1996: 184 : 569–577. Commentary: Moore JP, Koup RA. Chemoattractants attract HIV researchers. J Exp Med 1996: 184: 311. This is the first demonstration that the expression of CC chemokine receptors in T lymphocytes is regulated by activation. The study shows that interleukin-2 induces the expression of CCR1 and CCR2 and, in parallel, chemotactic migration in response to RANTES, MCP-1 and other CC chemokines in T lymphocytes. The effect of IL-2 is reversible: if IL-2 is withdrawn, receptor expression and chemotaxis decline, and are fully restored when it is added again. The data suggest that IL-2 mediated expansion may make antigen-activated T cells prone to recruitment, and may thus regulate the composition of lymphocytic infiltrate. Loetscher M, Gerber B, Loetscher P et al. Chemokine receptor specific for IP10 and Mig: Structure, function and expression in activated T lymphocytes. J Exp Med 1996: 184 : 963–969. Commentary: Mackay CR. Chemokine receptors and T cell chemotaxis. J Exp Med 1996: 184 : 799. The paper describes the cloning and characterization of the receptor for IP10 and Mig (CXCR3). The IP10/Mig receptor is highly expressed in IL-2 activated T lymphocytes, but is not detectable in resting T lymphocytes, B lymphocytes, monocytes and granulocytes. The findings reveal a mechanism for the selective recruitment of T lymphocytes in inflammation. Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, Dayer JM. CCR5 is characteristic of Th1 lymphocytes. Nature 1998: 391: 344–345. CCR5 is identified as a marker for Th1 cells and shown to be strongly expressed in the synovial membrane of patients with rheumatoid arthritis. Schaerli P, Willimann K, Lang AB, Lipp M, Loetscher P, Moser B. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp. Med 2000: 192: 1553–1562. Commentary: Mackay CR. Follicular homing T helper (Th) cells and the Th1/Th2 paradigm. J Exp Med 2000: 192: F31-F34. This paper shows that the chemokine receptor CXCR5 characterizes T lymphocytes with follicular homing and B cell helper capacity. It describes a mechanism by which T helper cells can reach the follicular compartment in secondary lymphoid organs, such as lymph nodes, Peyer's patches and spleen. In view of their properties, the cells are referred to as follicular B helper T cells (TFH cells). Schaerli P, Loetscher P, Moser B. Induction of follicular homing precedes effector Th cell development. J Immunol 2001: 167: 6082–6086. A follow up study (see reference 6) showing that TFH cells are a unique T helper cell subset. First, CXCR5 can be induced in all naïve CD4+ T cells and a subset of memory CD4+ T cells during activation, but is down-regulated during subsequent T helper cell expansion. Second, the TFH cells have a non-polarized phenotype, i.e. are not able to produce cytokines. Third, immunization with tetanus toxoid results in the accumulation of antigen-specific TFH cells in peripheral blood. These findings put the B cell compartment at the center stage of effector cell generation. Bardi G, Lipp M, Baggiolini M, Loetscher P. The T cell chemokine receptor CCR7 is internalized on stimulation with ELC, but not with SLC. Eur J Immunol 2001: 31: 3291–3297. This paper demonstrates the importance of receptor internalization for regulating chemokine responses in T lymphocytes and may explain how T lymphocytes that enter lymphoid tissues in response to SLC produced by high-endothelial venules can subsequently migrate in response to SLC and ELC expressed within T cell areas. Loetscher P, Pellegrino A, Gong JH et al. The Ligands of CXC Chemokine Receptor 3, I-TAC, Mig, and IP10, Are Natural Antagonists CCR3. J Biol Chem 2001: 276: 2986–2991. This study describes the identification of I-TAC, Mig and IP10 as antagonists for CCR3. This was the first demonstration that natural chemokines besides being agonists for their receptors can act as antagonists of other receptors. CCR3 antagonism is a mechanism for enhancing the polarization of T cell recruitment in inflammation. Loetscher P, Moser B, Baggiolini M. Chemokines and their receptors in lymphocyte traffic and HIV infection. Adv Immunol 2000: 74: 127–180. Moser B, Loetscher P. Lymphocyte traffic control by chemokines. Nature Immunol 2001: 2: 123–128. References 10 and 11 are review articles summarizing the importance of chemokines and chemokine receptors in the regulation of lymphocyte traffic in immunity and inflammation. Loetscher P, Clark-Lewis I. Agonistic and antagonistic activities of chemokines. J Leukocyte Biol 2001: 69: 881–884. This review article focuses on the fascinating new aspect of the regulation of chemokine activities: chemokines acting as natural antagonists for chemokine receptors thereby revealing a mechanism for polarizing cell recruitment during inflammatory and immune reactions. Moser B, Schaerli P, Loetscher P. CXCR5 + T cells: follicular homing takes center stage in T-helper-cell responses. Trends Immunol 2002: 23: 250–254. This is a very recent review article highlighting the role of CXCR5 and its ligand BCA-1 in the follicular homing and differentiation of primed, non-polarized T helper cells.