CCR7 on CD4+ T Cells Plays a Crucial Role in the Induction of Experimental Autoimmune Encephalomyelitis

Abstract

Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS. Myelin-specific CD4 Th lymphocytes are known to play a major role in both MS and its animal model experimental autoimmune encephalomyelitis (EAE). CCR7 is a critical element for immune cell trafficking and recirculation, that is, lymph node homing, under homeostatic conditions; blocking CCR7 central memory cells from egress of lymph nodes is a therapeutic approach in MS. To define the effect of CD4 T cell-specific constitutive deletion of CCR7 in the priming and effector phase in EAE, we used an active EAE approach in T cell reconstituted Rag1 mice, as well as adoptive transfer EAE, in which mice received in vitro-primed CCR7 or CCR7 myelin Ag TCR-transgenic 2d2 Th17 cells. Two-photon laser scanning microscopy was applied in living anesthetized mice to monitor the trafficking of CCR7-deficient and wild-type CD4 T cells in inflammatory lesions within the CNS. We demonstrate that CD4 T cell-specific constitutive deletion of CCR7 led to impaired induction of active EAE. In adoptive transfer EAE, mice receiving in vitro-primed CCR7 2d2 Th17 cells showed similar disease onset as mice adoptively transferred with CCR7 2d2 Th17 cells. Using two-photon laser scanning microscopy CCR7 and CCR7 CD4 T cells did not reveal differences in motility in either animal model of MS. These findings indicate a crucial role of CCR7 in neuroinflammation during the priming of autoimmune CD4 T cells but not in the CNS.

Transcription cofactor GRIP1 differentially affects myeloid cell–driven neuroinflammation and response to IFN-β therapy

“…5 A, upper panel; GRIP1 deletion efficiency is shown on the right as normalized read counts across "floxed" exon 11 of the Ncoa2 gene). In contrast, more heterogeneous activated CD45 + Cd11b + cells during EAE ( (Belikan et al, 2018;Salter and Stevens, 2017;Scheu et al, 2017). Interestingly, a pool of genes downregulated in WT mice during EAE but persisting in GRIP1-cKO mice (e.g., Gpr34, P2ry12; Fig.…”

T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis

“…For example, Ccr7 is known to participate in T cell-homeostasis and trafficking 42 and Ccr7 activation by its agonist Ccl21 directly amplifies antigen-specific T cell responses and T cell homeostatic proliferation 43 . Such functions would be relevant to autoimmunity, as Ccr7 promotes Th17-mediated autoimmune disease in experimental dry eye disease 44 , multiple sclerosis (EAE) 45 , and arthritis 46 . Thus, Nod2 may function similar to a co-stimulatory factor to temper the TCR-signaling threshold in order to control antigen-experienced T cells that are self-reactive pathogenic Th17 cells.…”

Epigenomics and Transcriptomics of Systemic Sclerosis CD4+ T cells reveal Long Range Dysregulation of Key Inflammatory Pathways mediated by disease-associated Susceptibility Loci

“…Specifically, Annexin A6 (ANXA6) has been described to be essential to CD4+ T cell proliferation via interleukin-2 signalling 65 . CCR7, on the other hand, has been predominantly implicated in T cell migration 66 and its deregulation in CD4+ T cells has been associated to several autoimmune diseases including SSc [67][68][69] . Finally, JUND encodes a TF that forms part of the AP-1 complex and has been previously described to regulate T cell proliferation and differentiation 70 .…”