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Impaired Trafficking of Gnai2^+/– and Gnai2^–/– T Lymphocytes: Implications for T Cell Movement within Lymph Nodes

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Signals generated by the engagement of chemoattractants with their cognate receptors orchestrate lymphocyte movements into and out of lymphoid organs and sites of inflammation. Yet, the role of chemokines in organizing lymphocyte movements in lymphoid organs is controversial. Recent evidence suggests that the extensive network of fibroblastic reticular cells within the T cell areas helps guide T cells. The expression of adhesion molecules and chemokines by fibroblastic reticular cells most likely facilitates their influence on T cell movements. Consistent with this hypothesis, CD4 T cells with defective chemokine receptor signaling move very differently within lymph nodes than do normal cells. For the imaging studies, we used CD4 T cells prepared from Gnai2^–/– mice, which lack G_i2 expression. We first demonstrate that CD4 as well as CD8 T cells from these mice are markedly defective in chemokine receptor signaling. Gnai2^–/– T cells have profound defects in chemokine-induced intracellular calcium mobilization, chemotaxis, and homing, whereas Gnai2^+/– T cells exhibit modest defects. Intravital imaging revealed that within the inguinal lymph nodes Gnai2^–/– CD4 T accumulate at the cortical ridge, poorly accessing the lymph node paracortex. They also lack the customary amoeboid-like cell movements and active membrane projections observed with normal CD4 T cells. These results demonstrate the importance of G_i2 for T lymphocyte chemokine receptor signaling and argue that local chemoattractants regulate the movement of CD4 T cells in lymph nodes.

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¹ Address correspondence and reprint requests to Dr. John H. Kehrl, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11B08, 10 Center Drive MSC 1876, Bethesda, MD 20892. E-mail address: jkehrl{at}niaid.nih.gov

² Abbreviations used in this paper: GPCR, G protein-coupled receptor; 3-D, three-dimensional; [Ca²⁺]_i, intracellular Ca²⁺ concentration; CMFDA, 5-chloromethylfluorescein diacetate; CMTMR, 5-(and 6-)(((4-chloromethyl)benzoyl) amino)tetramethylrhodamine; FRC, fibroreticular cell; HEV, high endothelial venule; S1P, sphingosine 1-phosphate.

³ The online version of this article contains supplemental material.

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