Reduced TCR‐dependent activation through citrullination of a T‐cell epitope enhances Th17 development by disruption of the STAT3/5 balance

Tibbitt, Christopher A.; Falconer, Jane; Stoop, Jeroen N.; Eden, Willem van; Robinson, John H.; Hilkens, Catharien M. U.

doi:10.1002/eji.201546217

Cited by 6 publications

(8 citation statements)

References 58 publications

(62 reference statements)

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“…Furthermore, when TCR signals are attenuated through the deletion of ITK, CD4 + T lymphocytes were more prone to differentiate into Forkhead box P3 (Foxp3) expressing regulatory Th cells (Tregs) over IL-17 producing cells (195). However, low levels of CD28 costimulation or antigen stimulation, as well as exposure to low potency antigens, have each been shown to favor the generation of IL-17 over IFN-γ (196,197) or IL-4 expressing effector CD4 + T cells (198). Therefore, the role of TCR signal strength in Th17 differentiation remains unclear.…”

Section: Tcr Signaling Strength and Cd4 + T Cell Differentiationmentioning

confidence: 99%

Regulation of T Helper Cell Fate by TCR Signal Strength

Bhattacharyya

Feng

2020

Front. Immunol.

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T cells are critical in orchestrating protective immune responses to cancer and an array of pathogens. The interaction between a peptide MHC (pMHC) complex on antigen presenting cells (APCs) and T cell receptors (TCRs) on T cells initiates T cell activation, division, and clonal expansion in secondary lymphoid organs. T cells must also integrate multiple T cell-intrinsic and extrinsic signals to acquire the effector functions essential for the defense against invading microbes. In the case of T helper cell differentiation, while innate cytokines have been demonstrated to shape effector CD4 + T lymphocyte function, the contribution of TCR signaling strength to T helper cell differentiation is less understood. In this review, we summarize the signaling cascades regulated by the strength of TCR stimulation. Various mechanisms in which TCR signal strength controls T helper cell expansion and differentiation are also discussed.

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Section: Tcr Signaling Strength and Cd4 + T Cell Differentiationmentioning

confidence: 99%

Regulation of T Helper Cell Fate by TCR Signal Strength

Bhattacharyya

Feng

2020

Front. Immunol.

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“…For example, citrullinated aggrecan reduced T cell proliferation but enhanced Th17 differentiation, which was promoted by low-strength TCR signalling [122]. For example, citrullinated aggrecan reduced T cell proliferation but enhanced Th17 differentiation, which was promoted by low-strength TCR signalling [122].…”

Section: Quality Of Dc-t Cell Interactionmentioning

confidence: 99%

“…As mentioned earlier, citrullination of self-antigens modulates the quality of MHC binding and TCR signalling. For example, citrullinated aggrecan reduced T cell proliferation but enhanced Th17 differentiation, which was promoted by low-strength TCR signalling [122]. TCR signalling strength can also determine the severity of arthritis in murine models of RA [123,124].…”

Section: Quality Of Dc-t Cell Interactionmentioning

confidence: 99%

Dendritic cells, T cells and their interaction in rheumatoid arthritis

Wehr

Purvis

Law

et al. 2019

Clinical and Experimental Immunology

127

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Dendritic cells (DCs) are the key professional antigen-presenting cells which bridge innate and adaptive immune responses, inducing the priming and differentiation of naive to effector CD4 + T cells, the cross-priming of CD8 + T cells and the promotion of B cell antibody responses. DCs also play a critical role in the maintenance of immune homeostasis and tolerance. DC-T cell interactions underpin the generation of an autoimmune response in rheumatoid arthritis (RA). Here we describe the function of DCs and review evidence for DC and T cell involvement in RA pathogenesis, in particular through the presentation of self-peptide by DCs that triggers differentiation and activation of autoreactive T cells. Finally, we discuss the emerging field of targeting the DC-T cell interaction for antigen-specific immunotherapy of RA.

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“…First, Th1 and Th17 signals could both be upregulated and both suppress the other, and this could be described as "sleeping with enemy". In vitro, autoreactive PTM peptide promotes Th17 induction in RA [45,46]. Moreover, autoreactive T-cell responses to type II collagen show skewing toward Th1 [12].…”

Section: Discussionmentioning

confidence: 96%

Clinical Impact of Interferon-γ in Anti-Citrullinated Protein Antibody-Positive Rheumatoid Arthritis

Lee

Min

et al. 2020

Preprint

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Background: CD4+ T cells are crucial for the pathogenesis of rheumatoid arthritis (RA). The roles of gene overexpression in CD4+ T cells and the predictive roles of Th1- and Th17-related cytokines have not been clearly defined in patients with RA. Here, we investigated gene expression levels in CD4+ T cells in methotrexate (MTX)-naïve early RA (eRA) and evaluated changes in CD4+ T-cell-related cytokines during eRA. Methods: Patients with anti-citrullinated protein antibody (ACPA)-positive MTX-naïve eRA were recruited. Patients with osteoarthritis were evaluated as controls. Microarray analysis was used to identify overexpressed genes in CD4+ T cells, and reverse transcription quantitative polymerase chain reaction was used to validate the identified genes. Plasma cytokine levels were measured, and correlations with disease activity were assessed.Results: Thirty-four genes showed overexpression in CD4+ T cells from patients with ACPA-positive MTX-naïve eRA compared with controls. Nineteen were related to interferon (IFN)-γ, and nine were related to interleukin (IL)-17A; five were related to both IFN-γ and IL-17A. Plasma levels of five cytokines were elevated in the ACPA-positive MTX-naïve eRA group compared with those in the control group, and C-X-C motif chemokine ligand 10 was significantly elevated in the ACPA-positive MTX-naïve eRA group compared with that in the established active RA and OA groups. In established RA with low disease activity, the drug-free remission group/drug reduction group showed significantly lower IFN-γ and IL-17A levels than the drug maintenance group and relapse after drug reduction group. Conclusion: Our T2 research of IFN-γ emphasized that, not only the Th17 immune response, but the Th1 immune response is also very important for the RA pathogenesis. Concurrent increase in IFN-γ and IL-17 were observed in active stage of ACPA-positive MTX-naïve eRA, and the plasma levels of them could be useful for new clinical biomarkers before and/or after treatment of RA.

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Reduced TCR‐dependent activation through citrullination of a T‐cell epitope enhances Th17 development by disruption of the STAT3/5 balance

Cited by 6 publications

References 58 publications

Regulation of T Helper Cell Fate by TCR Signal Strength

Regulation of T Helper Cell Fate by TCR Signal Strength

Dendritic cells, T cells and their interaction in rheumatoid arthritis

Clinical Impact of Interferon-γ in Anti-Citrullinated Protein Antibody-Positive Rheumatoid Arthritis

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