Cutting Edge: Hierarchy of Chemokine Receptor and TCR Signals Regulating T Cell Migration and Proliferation

Abstract

Chemokines play an important role in establishing the distribution of lymphocyte subpopulations in primary and secondary lymphoid tissues and in the recruitment of leukocytes to sites of inflammation. However, the potential of chemokines to down-regulate immune responses has not been demonstrated. We now show that certain chemokine gradients have the potential to suppress T cell activation by preventing formation of the immunological synapse, the specialized cell-cell junction that forms before a T cell can be fully activated. Our data reveals an immunosuppressive potential of chemokines engaging the CXCR3 and CCR7 receptors, but not the CXCR4, CCR2, CCR4, or CCR5 receptors. These results suggest a novel mechanism for T cell ignorance of agonist MHC-peptide complexes based on dominant chemokine gradients.

L-Selectin-Dependent Lymphoid Occupancy Is Required to Induce Alloantigen-Specific Tolerance

“…Indeed, in preliminary experiments, Hox11 Ϫ/Ϫ mice lacking a spleen had prolonged allograft survival, and anti-CD62L prevented graft survival (Y. Bai and J. S. Bromberg, unpublished results). Why the LN may be more tolerogenic than the spleen is not certain, but it is interesting to note that CCR7 engagement in the LN may specifically be immunosuppressive and prevent formation of the immunological synapse (10). Thus, there may by distinct secondary lymphoid organs with tolerogenic or nontolerogenic potentials.…”

Tumor Necrosis Factor Blockade in Chronic Murine Tuberculosis Enhances Granulomatous Inflammation and Disorganizes Granulomas in the Lungs

“…Results of the present study using a well-established murine model of chronic tuberculosis suggest that increased inflammation and disorganization of the granuloma structure occur in the very early stage of TNF blockade therapy, when the tissue bacterial burdens are comparable among the experimental and control mouse groups. Since excessive chemokine production at the site of inflammation can result in mistrafficking of immune cells (6,32), it is possible that the enhanced inflammatory response observed in TNF-neutralized mice (a component of which is increased expression of specific chemokines) could lead to disorganization of the granulomatous structure. In the case of the B-lymphoid nodules, it is noteworthy that chemoattraction of CCR6 ϩ B lymphocytes plays a critical role in the formation of intestine-associated B-lymphoid structures (43).…”

CCR7 Expression in Developing Thymocytes Is Linked to the CD4 versus CD8 Lineage Decision

“…Chemokine signaling can modulate TCR signaling in mature T cells (40,41). Because the strength and duration of TCR signaling may be a determinant of the CD4-vs CD8-lineage choice, this raises the possibility that the differential expression of CCR7 in CD4 ϩ CD8 ϩ thymocytes may differentially modulate TCR signaling during MHC-I vs MHC-II selection and consequently influence CD4/CD8-lineage choice.…”