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

Glatigny S, Duhen R, Arbelaez C, Kumari S, Bettelli E - Sci Rep (2015)

Bottom Line: Regulatory T cells (Treg) can control effector T cells and limit the progression of CNS autoimmunity.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Benaroya Research Institute, Immunology Program, Seattle WA 98101, USA [2] University of Washington, Department of Immunology, Seattle WA 98105, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Deletion of Itga4 in Foxp3+ cells does not interfere with Tregs differentiation and functions at steady state.(A) and (B) Spleen, LN, mesenteric LN (mLN) and Thymus were collected from Foxp3Cre and Foxp3Cre Itga4fl/fl mice. (A) Frequency of Foxp3+ cells among CD4+ T cells (Top) and absolute numbers of CD4+ Foxp3+ regulatory T cells (Bottom) from these tissues were calculated from two independent experiments with 4–6 mice per group. (B) Expression of selective markers on CD4+ Foxp3+ T cells from Foxp3Cre (dark line) and Foxp3Cre Itga4fl/fl mice (red line). (C) Tregs from Itga4fl/fl (open circles) and CD4Cre Itga4fl/fl mice (filled circles) were tested for their suppressive activity on CD4+ CD25− cells proliferation in vitro. Mean proliferation (cpm ± SD) of Tregs alone, Teffs alone (open triangles) or Teffs in the presence of different ratios of Tregs/Teffs is shown and representative of 2 independent experiments.
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f2: Deletion of Itga4 in Foxp3+ cells does not interfere with Tregs differentiation and functions at steady state.(A) and (B) Spleen, LN, mesenteric LN (mLN) and Thymus were collected from Foxp3Cre and Foxp3Cre Itga4fl/fl mice. (A) Frequency of Foxp3+ cells among CD4+ T cells (Top) and absolute numbers of CD4+ Foxp3+ regulatory T cells (Bottom) from these tissues were calculated from two independent experiments with 4–6 mice per group. (B) Expression of selective markers on CD4+ Foxp3+ T cells from Foxp3Cre (dark line) and Foxp3Cre Itga4fl/fl mice (red line). (C) Tregs from Itga4fl/fl (open circles) and CD4Cre Itga4fl/fl mice (filled circles) were tested for their suppressive activity on CD4+ CD25− cells proliferation in vitro. Mean proliferation (cpm ± SD) of Tregs alone, Teffs alone (open triangles) or Teffs in the presence of different ratios of Tregs/Teffs is shown and representative of 2 independent experiments.

Mentions: It is unclear whether the control of effector T cell populations (Teff) occurs in the peripheral organs or in the CNS. To address this question and look at the specific effect of Itga4 on Tregs, we crossed Itga4fl/fl mice with Foxp3Cre-YFP mice1112. In these animals, Cre-mediated deletion of Itga4 was efficient and specific to Foxp3+ regulatory T cells (Figure 2B), leaving intact Itga4 expression by effector T cells (data not shown). Because Itga4 has been implicated in various processes including T cell migration and activation1314, we examined the effect of Itga4 deletion on Treg distribution in lymphoid organs. Deletion of Itga4 on Treg cells did not alter their thymic and peripheral distribution (Figure 2A). We also investigated whether Itga4 deletion could modulate the phenotype of Treg cells and the arsenal of surface molecules that they express. We observed similar levels of CD103, CD25, CD11a, GITR, CD62L, Helios, CTLA4 and CCR6 in Itga4-competent or -deficient (YFP+) Tregs (Figure 2B). Next, we determined whether Itga4 could inhibit the function of Tregs. To address this possibility, we compared the capacity of Itga4-deficient or -competent Tregs to suppress the proliferation of effector T cells in vitro. Both WT and Itga4-deficient Tregs were equally effective at controlling the proliferation of Teff cells (Figure 2C), indicating that Itga4 neutralization do not limit the function of Tregs.


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

Glatigny S, Duhen R, Arbelaez C, Kumari S, Bettelli E - Sci Rep (2015)

Deletion of Itga4 in Foxp3+ cells does not interfere with Tregs differentiation and functions at steady state.(A) and (B) Spleen, LN, mesenteric LN (mLN) and Thymus were collected from Foxp3Cre and Foxp3Cre Itga4fl/fl mice. (A) Frequency of Foxp3+ cells among CD4+ T cells (Top) and absolute numbers of CD4+ Foxp3+ regulatory T cells (Bottom) from these tissues were calculated from two independent experiments with 4–6 mice per group. (B) Expression of selective markers on CD4+ Foxp3+ T cells from Foxp3Cre (dark line) and Foxp3Cre Itga4fl/fl mice (red line). (C) Tregs from Itga4fl/fl (open circles) and CD4Cre Itga4fl/fl mice (filled circles) were tested for their suppressive activity on CD4+ CD25− cells proliferation in vitro. Mean proliferation (cpm ± SD) of Tregs alone, Teffs alone (open triangles) or Teffs in the presence of different ratios of Tregs/Teffs is shown and representative of 2 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4296287&req=5

f2: Deletion of Itga4 in Foxp3+ cells does not interfere with Tregs differentiation and functions at steady state.(A) and (B) Spleen, LN, mesenteric LN (mLN) and Thymus were collected from Foxp3Cre and Foxp3Cre Itga4fl/fl mice. (A) Frequency of Foxp3+ cells among CD4+ T cells (Top) and absolute numbers of CD4+ Foxp3+ regulatory T cells (Bottom) from these tissues were calculated from two independent experiments with 4–6 mice per group. (B) Expression of selective markers on CD4+ Foxp3+ T cells from Foxp3Cre (dark line) and Foxp3Cre Itga4fl/fl mice (red line). (C) Tregs from Itga4fl/fl (open circles) and CD4Cre Itga4fl/fl mice (filled circles) were tested for their suppressive activity on CD4+ CD25− cells proliferation in vitro. Mean proliferation (cpm ± SD) of Tregs alone, Teffs alone (open triangles) or Teffs in the presence of different ratios of Tregs/Teffs is shown and representative of 2 independent experiments.
Mentions: It is unclear whether the control of effector T cell populations (Teff) occurs in the peripheral organs or in the CNS. To address this question and look at the specific effect of Itga4 on Tregs, we crossed Itga4fl/fl mice with Foxp3Cre-YFP mice1112. In these animals, Cre-mediated deletion of Itga4 was efficient and specific to Foxp3+ regulatory T cells (Figure 2B), leaving intact Itga4 expression by effector T cells (data not shown). Because Itga4 has been implicated in various processes including T cell migration and activation1314, we examined the effect of Itga4 deletion on Treg distribution in lymphoid organs. Deletion of Itga4 on Treg cells did not alter their thymic and peripheral distribution (Figure 2A). We also investigated whether Itga4 deletion could modulate the phenotype of Treg cells and the arsenal of surface molecules that they express. We observed similar levels of CD103, CD25, CD11a, GITR, CD62L, Helios, CTLA4 and CCR6 in Itga4-competent or -deficient (YFP+) Tregs (Figure 2B). Next, we determined whether Itga4 could inhibit the function of Tregs. To address this possibility, we compared the capacity of Itga4-deficient or -competent Tregs to suppress the proliferation of effector T cells in vitro. Both WT and Itga4-deficient Tregs were equally effective at controlling the proliferation of Teff cells (Figure 2C), indicating that Itga4 neutralization do not limit the function of Tregs.

Bottom Line: Regulatory T cells (Treg) can control effector T cells and limit the progression of CNS autoimmunity.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Benaroya Research Institute, Immunology Program, Seattle WA 98101, USA [2] University of Washington, Department of Immunology, Seattle WA 98105, USA.

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.

No MeSH data available.


Related in: MedlinePlus