CCR2 Signal Facilitates Thymic Egress by Priming Thymocyte Responses to Sphingosine-1-Phosphate

Abstract

The signal mediated by sphingosine-1-phosphate receptor 1 (S1P1) is essential but seemingly insufficient for thymic export of newly generated T cells. Here, we reported the identification of CCR2 as an additional regulator of this process. CCR2 showed a markedly increased expression in the most mature subset of single-positive (SP) thymocytes. Its deficiency led to a reduction of recent thymic emigrants in the periphery and a simultaneous accumulation of mature SP cells in the thymus. The CCR2 signaling promoted thymic emigration primarily through modulating the chemotactic responses to S1P1 engagement. On the one hand, the chemokinesis induced by CCR2 activation endowed thymocytes with enhanced capacity to respond to S1P-induced migration. On the other hand, CCR2 signaling through Stat3 augmented forkhead box O1 activity, leading to increased expression of S1P1. Taken together, the present study highlights a unique and novel function of CCR2 signaling in the regulation of thymic egress.

Tissue-specific transcriptional imprinting and heterogeneity in human innate lymphoid cells revealed by full-length single-cell RNA-sequencing

“…Other genes in the module were particularly expressed in blood ILC2 or blood and tonsil ILC2, including transcripts for receptors involved in cell trafficking and migration such as the prototypical ILC2 marker CRTH2 ( PTGDR2 ), S1PR2 and CCR2 , the latter shown to be involved in the regulation of S1P receptors. 29 The TNF family-related transcripts TNFSF10 (encoding TRAIL) and TNFRSF19 (encoding TROY) were also highly expressed by blood and tonsil ILC2, as well as CD200R1 , possibly acting as an inhibitory receptor for human blood and tonsil ILC2. Another ILC2-related module was less restricted to ILC2 but still contained transcripts relevant for ILC2 biology, particularly for the potential negative regulation of these cells; IL10RA , 30 KLRG1 , 31 PTGER2 , 32 ANXA1 33 as well as LGALS1 , encodes the immunosuppressive molecule galectin-1.…”

The molecular structure and role of CCL2 (MCP‐1) and C‐C chemokine receptor CCR2 in skeletal biology and diseases

“…In the immune system, it regulates the expression of T‐cell inflammatory cytokines and promotes the differentiation of T‐cells into T‐helper 17 cells (Th17) during inflammation (Bakos et al, 2017). CCL2 also promotes the export of mature thymocytes by enhancing their directional movement (Aili et al, 2018) and mediates the pathogenesis of asthma via neutrophil apoptosis (Yang et al, 2012). CCL2 is considered a major factor in the pathogenesis of vascular disease involving human cytomegalovirus (HCMV) (Stern & Slobedman, 2008).…”

Thymic Egress Is Regulated by T Cell-Derived LTβR Signal and via Distinct Thymic Portal Endothelial Cells

“…These include chemokines Cxcl9 and Cxcl10, and sphingosine kinase Sphk1, which is important for S1P production. Given the selectively high expression of Cxcl9/10 receptor on the most mature thymocytes ( 21 , 22 ) and the well-established role of S1P in thymic egress ( 23 ), these results might indicate a special local niche attracting mature thymocytes for their egress. In addition, a bigger question that remains largely elusive is how seemingly the same crosstalk between T cells and thymic ECs via the same LT/LIGHT-LTβR axis could control both thymic homing and egress via iTPECs and eTPECs, respectively.…”

“…Chemokines play important roles for thymic homing of HPCs and egress of mature thymocytes ( 20 , 21 ). We found both Cxcl9 and Cxcl10 were selectively expressed in C2 rather than in C6 or other subsets ( Supplementary Figures 6B, C ).…”

“…We found both Cxcl9 and Cxcl10 were selectively expressed in C2 rather than in C6 or other subsets ( Supplementary Figures 6B, C ). In fact, Cxcr3, the receptor of Cxcl9/10, is just highly expressed on the most mature thymocytes ( 21 , 22 ), suggesting a possibility of thymic egress regulation via Cxcl9/10-Cxcr3 signaling axis. These suggest that C2 subset might be a source of chemokines to guide mature thymocytes for their egress.…”