Integrin alpha L controls the homing of regulatory T cells during CNS autoimmunity in the absence of integrin alpha 4

Abstract

Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), results from an autoimmune attack of the central nervous system (CNS) by effector T helper (Th) 1 and Th17 cells. Regulatory T cells (Treg) can control effector T cells and limit the progression of CNS autoimmunity. Integrin alpha 4 (Itga4) is critical for the entry of Th1 but not Th17 cells into the CNS during EAE. Whether Itga4 controls the homing of Tregs in the CNS and whether Tregs can limit Th17-mediated EAE has, however, not been addressed. Through selective elimination of Itga4 in Foxp3-expressing cells, we show here that Tregs can suppress Th17-mediated EAE and enter into the CNS independently of Itga4. Furthermore, similarly to Th17 cells and in contrast to Th1 cells, Tregs depend on LFA-1 for their entry into the CNS in the absence of Itga4. Therefore, these data suggest that the efficacy of Itga4 neutralization on MS progression may be associated with the prevention of Th1 cells and the maintenance of Tregs migration into the CNS.

Cutting Edge: Integrin α4 Is Required for Regulatory B Cell Control of Experimental Autoimmune Encephalomyelitis

“…CNS mononuclear cells were isolated as previously described (7). Intracellular cytokine staining was performed as described previously (7).…”

“…Intracellular cytokine staining was performed as described previously (7). Cells were acquired on LSRII (BD Biosciences), and data were analyzed with FlowJo software.…”

“…In addition to disease-promoting activities, emerging evidence support the notion that B cells can have regulatory functions (3–6). Pathogenic T cells are controlled by different regulatory mechanisms, which include, regulatory T cells (Treg) and B cells (Breg) (7, 8). Bregs produce regulatory cytokines and express inhibitory molecules that suppress pathogenic T cells and autoreactive B cells (3, 5, 6, 9).…”

Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells

“…We found the upregulation on CD8 + CD45RC low/-T cells from anti-CD45RC-treated tolerant rats of genes involved in immune function; the genes included Itgal and Itgb2, which combine to control Treg homing (32); Tnfrsf25, which is described as highly expressed by CD4 + Tregs and a therapeutic target to promote Treg expansion (33,34); and Tnf, Cxcr3, or Ccl9 ( Figure 5C). Finally, we observed the downregulation of activation markers such as Cd38, Cd69, Cd28, and Cd40l and the downregulation of chemokine receptor Ccr9 and chemokine Cxcl10 and Cxcl16.…”

Control of Regulatory T Cell Migration, Function, and Homeostasis

“…In addition to these chemokine receptors, Treg cells express surface integrins that influence their localization and function during inflammation. For instance, Treg cells express high levels of αLβ2 integrin (LFA-1) and α4β1 integrin (VLA-4), and together these can help direct Treg cell migration to inflamed tissues (55). …”