Retinoic acid suppresses IL‐17 production and pathogenic activity of γδ T cells in CNS autoimmunity

Abstract Background All-trans retinoic acid (RA) plays a crucial role in promoting Foxp3+ Treg generation while reciprocally inhibiting Th1/Th17 generation. Our previous research highlighted that in the face of inflammatory conditions, RA plays a contrary role where it aggravates intestinal inflammation by promoting interferon (IFN) γ and interleukin (IL)-17 differentiation in vitro. Methods In this study we translated our in vitro results into a clinical setting where we estimated mucosal and serum RA levels along with the immunophenotypic profile (IL-17, IFNγ, Foxp3, IL-10) in adaptive (CD4, CD8) and innate-like T cells (mucosal associated invariant T cells and γδ T cells) in patients with ulcerative colitis in remission or with active inflammation. Results This is the first study to estimate RA levels in the human gut and shows that patients with active disease had increased mucosal RA levels as compared with patients in remission (4.0 vs 2.5 ng/mL; P < 0.01) and control patients (3.4 vs 0.8 ng/mL; P < 0.0001). This effect was accompanied by significantly elevated IL-17 and IFNγ in tissue CD4+, CD8+, mucosal associated invariant T+ cells, and γδ + T cells. Moreover, the raised RA levels in patients with active disease showed a positive correlation with proinflammatory cytokines (IL-17, IFNγ) and a negative correlation with IL-10. We also found that RA negatively correlated with IL-9, thereby reinstating our previous finding that RA inhibits Th9 differentiation. Conclusions These data confirm our previous in vitro results that in the presence of inflammation, RA plays a crucial role in maintaining gut inflammation by upregulating proinflammatory markers.

Download Full-text

CS02-5. Retinoic acid enhances IL-22 production by(γδ) T cells and protects against colitis

Cytokine ◽

10.1016/j.cyto.2011.07.311 ◽

2011 ◽

Vol 56 (1) ◽

pp. 6

Author(s):

Lisa A Mielke ◽

Alicja Misiak ◽

Caroline E Sutton ◽

Kingston H G Mills

Keyword(s):

T Cells ◽

Retinoic Acid ◽

Γδ T Cells

Download Full-text

The retinoic acid receptor drives neuroinflammation and fine tunes the homeostasis of interleukin-17-producing T cells

10.1101/2020.08.12.247510 ◽

2020 ◽

Author(s):

Rasmus Agerholm ◽

John Rizk ◽

Darshana Kadekar ◽

Annie Borch ◽

Sine Reker Hadrup ◽

...

Keyword(s):

T Cells ◽

Retinoic Acid ◽

Cell Cycle Progression ◽

Retinoic Acid Receptor ◽

Γδ T Cells ◽

Interleukin 17 ◽

T Helper 17 ◽

Acid Receptor ◽

Expression Of Genes ◽

The Brain

AbstractThe vitamin A metabolite retinoic acid (RA) and its receptor (RAR) are one of the key interactions regulating cellular immunity and neural signaling. Whether endogenous RA-RAR interactions contribute to the development of neuroinflammation and diseases like multiple sclerosis, remains to be elucidated. Herein, we used the murine experimental autoimmune encephalomyelitis (EAE) model and an established genetic RAR silencing approach to decipher its role in pathogenic T cell responses. We show that RAR is necessary for the development of interleukin(IL)-17-driven, cell-mediated immunopathology in the brain and that it fine tunes the homeostasis of IL-17-producing gamma delta (γδT17) and CD4+ T cells (TH17). At steady-state, RAR was required in the γδT17 compartment to sustain optimal cell numbers and maintain expression of genes involved in cell cycle progression. In contrast, RAR negatively regulated T helper-17 (TH17) cell homeostasis. Our data show that RAR is required during the early phases of EAE in order to induce a γδT17 response and that its activity is necessary throughout the course of the disease to allow TH17 and γδT17 cells to infiltrate the brain. This is correlated with failure of RAR deficient cells to express surface integrin-alpha4, a major brain homing molecule. Collectively, our work demonstrates that endogenous RA-RAR interactions are important for the homeostasis of IL-17-producing T cells and necessary for their pathogenicity during neuroinflammation.One sentence summaryRetinoic acid receptor activity was required on IL-17-producing CD4+ and γδ T cells to induce their neuropathogenicity, and to regulate both positively and negatively their homeostasis.

Download Full-text

Faculty Opinions recommendation of Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718011907.793498221 ◽

2014 ◽

Author(s):

De'Broski Herbert

Keyword(s):

T Cells ◽

Retinoic Acid ◽

Intestinal Inflammation ◽

Γδ T Cells ◽

Innate Lymphoid Cells ◽

Lymphoid Cells

Download Full-text

Faculty Opinions recommendation of Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718011907.793498918 ◽

2014 ◽

Author(s):

Jay Kolls ◽

Pawan Kumar

Keyword(s):

T Cells ◽

Retinoic Acid ◽

Intestinal Inflammation ◽

Γδ T Cells ◽

Innate Lymphoid Cells ◽

Lymphoid Cells

Download Full-text

Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation

Journal of Experimental Medicine ◽

10.1084/jem.20121588 ◽

2013 ◽

Vol 210 (6) ◽

pp. 1117-1124 ◽

Cited By ~ 161

Author(s):

Lisa A. Mielke ◽

Sarah A. Jones ◽

Mathilde Raverdeau ◽

Rowan Higgs ◽

Anna Stefanska ◽

...

Keyword(s):

T Cells ◽

Retinoic Acid ◽

Intestinal Inflammation ◽

Γδ T Cells ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Enhanced Production ◽

Molecular Events

Retinoic acid (RA), a vitamin A metabolite, modulates mucosal T helper cell responses. Here we examined the role of RA in regulating IL-22 production by γδ T cells and innate lymphoid cells in intestinal inflammation. RA significantly enhanced IL-22 production by γδ T cells stimulated in vitro with IL-1β or IL-18 and IL-23. In vivo RA attenuated colon inflammation induced by dextran sodium sulfate treatment or Citrobacter rodentium infection. This was associated with a significant increase in IL-22 secretion by γδ T cells and innate lymphoid cells. In addition, RA treatment enhanced production of the IL-22–responsive antimicrobial peptides Reg3β and Reg3γ in the colon. The attenuating effects of RA on colitis were reversed by treatment with an anti–IL-22 neutralizing antibody, demonstrating that RA mediates protection by enhancing IL-22 production. To define the molecular events involved, we used chromatin immunoprecipitation assays and found that RA promoted binding of RA receptor to the IL-22 promoter in γδ T cells. Our findings provide novel insights into the molecular events controlling IL-22 transcription and suggest that one key outcome of RA signaling may be to shape early intestinal immune responses by promoting IL-22 synthesis by γδ T cells and innate lymphoid cells.

Download Full-text