Lymphotactin: a key regulator of lymphocyte trafficking during acute graft rejection

Abstract

The attraction of leucocytes to allografts is essential for rejection. The process is controlled by chemokines. In order to clarify the role of lymphotactin (a cytokine that represents a novel branch of the chemokine superfamily) in regulating leucocyte trafficking during graft rejection, we used rat renal transplantation models to examine its gene expression and the distribution of lymphotactin-expressing cells in renal grafts. Lymphotactin mRNA was upregulated strongly in acutely rejecting renal allografts. The mRNA was undetectable in isografts, chronically rejecting renal allografts or normal kidney. Once lymphotactin was expressed, large numbers of infiltrating lymphocytes were seen. Moreover extended studies demonstrated that in cultured rat spleen cells the expression of lymphotactin mRNA was markedly induced by phytohaemagglutinin (PHA) or phorbol myristate acetate (PMA), and such induction was inhibited by the immunosuppressive drugs FK506 and cyclosporin. Collectively, these observations provide new evidence demonstrating that lymphotactin is a key regulator of lymphocyte motility and adhesiveness during acute allograft rejection. FK506 and cyclosporin inhibition of lymphotactin expression is likely to represent an important molecular mechanism of the action of the drugs.

CD8+αβ+ T Cells That Lack Surface CD5 Antigen Expression Are a Major Lymphotactin (XCL1) Source in Peripheral Blood Lymphocytes

“…Nevertheless, the interest in XCL1 has recently received a new impetus due to the identification of its receptor (48) and to several investigations that indicated its possible role as a potent adjuvant in cancer immunotherapy (25-29, 49 -51). Data are also rapidly accumulating in other immunopathologic settings, and XCL1 has been shown to be involved in some autoimmune disorders and in transplant rejection in both experimental models and humans (52)(53)(54)(55)(56). Two major problems still need to be solved.…”

“…These observations must be substantiated by more careful screening of the expression of a large panel of chemokines/cytokines by CD3 ϩ CD8 ϩ CD5 Ϫ lymphocytes; in any case, further investigation will also be needed in different immunopathologic settings to clarify the role of this subset within the physiology of immune function. On the one hand, in fact, several observations would seem to point to its possible implication in antiviral immunity in view of its expansion in several viral infections (40, 66 -68); on the other, the independent observations of an increase in this subset in renal transplant recipients undergoing kidney rejection (69) and of the possible role played by XCL1 in transplant rejection (54,55) may indicate a new potential target in selected immunopathologic settings.…”

Chemokine Expression Dynamics in Mycobacterial (Type-1) and Schistosomal (Type-2) Antigen-Elicited Pulmonary Granuloma Formation

“…Lymphotactin is presently the sole representative of the XCR CK class and a well-described chemoattractant for both NK cells and T lymphocytes. [45][46][47] Enhanced lymphotactin gene expression has been reported in an animal model of glomerulonephritis 48 and is produced by T cells, 49 NK cells, 50 and mast cells. 51 Although lymphotactin exerts a co-stimulatory activity on CD8ϩ T-cells, it was recently identified as an inhibitor of CD4 ϩ T-cell proliferation and Th1 responses, causing decreased expression of IL-2, IL-2R␣, and IFN-␥ but not IL-4 and IL-13.…”

Prolonged Allograft Survival in TNF Receptor 1-Deficient Recipients Is Due to Immunoregulatory Effects, Not to Inhibition of Direct Antigraft Cytotoxicity

“…These results suggest that the expression of these chemokines is regulated, either directly or indirectly, by TNF-R1-mediated signals. Elevated levels of RANTES, IP-10, and Ltn have been demonstrated in allograft rejection in human and experimental models, and regulation of the production of these mediators through TNF-R1 immunomodulatory signals may be an important mechanism by which TNF-␣ and LT␣ regulate effector functions in allograft rejection (32)(33)(34)(35)(36)(37). Interestingly, there is evidence that RANTES, IP-10, and Ltn may be preferentially expressed by activated CD8 T cells, and there are also data suggesting that IP-10 may be important for CD8 T cell-mediated antitumor and antiviral effector functions (38 -42).…”