The CXC Chemokine Receptor 3 Inhibits Autoimmune Cholangitis via CD8+ T Cells but Promotes Colitis via CD4+ T Cells

Abstract

CXC chemokine receptor 3 (CXCR3), a receptor for the C-X-C motif chemokines (CXCL) CXCL9, CXCL10, and CXCL11, which not only plays a role in chemotaxis but also regulates differentiation and development of memory and effector T cell populations. Herein, we explored the function of CXCR3 in the modulation of different organ-specific autoimmune diseases in interleukin (IL)-2 receptor deficiency (CD25−/−) mice, a murine model for both cholangitis and colitis. We observed higher levels of CXCL9 and CXCL10 in the liver and colon and higher expression of CXCR3 on T cells of the CD25−/− mice compared with control animals. Deletion of CXCR3 resulted in enhanced liver inflammation but alleviated colitis. These changes in liver and colon pathology after CXCR3 deletion were associated with increased numbers of hepatic CD4+ and CD8+ T cells, in particular effector memory CD8+ T cells, as well as decreased T cells in mesenteric lymph nodes and colon lamina propria. In addition, increased interferon-γ response and decreased IL-17A response was observed in both liver and colon after CXCR3 deletion. CXCR3 modulated the functions of T cells involved in different autoimmune diseases, whereas the consequence of such modulation was organ-specific regarding to their effects on disease severity. Our findings emphasize the importance of extra caution in immunotherapy for organ-specific autoimmune diseases, as therapeutic interventions aiming at a target such as CXCR3 for certain disease could result in adverse effects in an unrelated organ.

Dynamic Network Biomarker of Pre-Exhausted CD8+ T Cells Contributed to T Cell Exhaustion in Colorectal Cancer

“…In addition, we observed that CXCL13 , as the ligand of terminal Tex cells, interacted with CXCR3 as the receptor of pre-exhausted T cells. CXCR3 , as a co-receptor for the chemokine CXCL13 , is chemotactic and involved in regulating the differentiation and development of memory cells and effector T cells ( 31 ). This indicates that cellular communication of terminal Tex cells with pre-exhausted T cells might lead to differentiation toward exhaustion.…”

Therapeutic and Diagnostic Implications of T Cell Scarring in Celiac Disease and Beyond

“…The axes of IFN-g:CXCL10:CXCR3 and CCL4:CCR5 are thus likely to recruit gluten-specific CD4 + T cells into the celiac lesion. Although disease-specific cells have not been demonstrated in most other autoimmune diseases, increased numbers of CCR5 + , CXCR3 + , CD4 + T cells or increased levels of their receptor ligands have been reported in patient cohorts with different autoimmune conditions, including T1D [57], MS [58,59], RA [60,61], SLE [62], Ssc [63], psoriasis [64,65], and in several murine autoimmune models [66,67].…”

C-X-C Motif Chemokine Ligand 9 and Its CXCR3 Receptor Are the Salt and Pepper for T Cells Trafficking in a Mouse Model of Gaucher Disease

“…This study identified a direct role of the CXCL9-CXCR3 axis in aiming the excess tissue recruitment of T cells in the Gba1 9V/− mouse. CXCR3 is an attractive therapeutic target for treating T cell-mediated inflammatory diseases [ 83 , 84 , 90 , 91 , 92 , 93 , 94 , 95 , 96 ]. CXCL9-mediated ex vivo and in vivo chemotaxis of T cell subsets (i.e., CD4 + T and CD8 + T cells) in the presence or absence of mouse anti-CXCR3 antibodies showed that targeting CXCR3 caused marked reduction in CXCL9-mediated enhanced tissue recruitment of T cell subsets in GD.…”