TCR Affinity Biases Th Cell Differentiation by Regulating CD25, Eef1e1, and Gbp2

Kotov, Dmitri I.; Mitchell, Jason S.; Pengo, Thomas; Ruedl, Christiane; Way, Sing Sing; Langlois, Ryan A.; Fife, Brian T.; Jenkins, Marc K.

doi:10.4049/jimmunol.1801609

Cited by 54 publications

(39 citation statements)

References 74 publications

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“…Although earlier reports suggested that Tfh cell differentiation requires high TCR signal strength, recent work supports the idea that Tfh cells develop across a wide range of signal strengths, while increasing TCR signal intensity favors Th1 generation (4)(5)(6)(7)(8)(9)(10)(11). A central difficulty in reconciling these findings is the use of different TCR tg systems as well as immunization and infection models that may induce distinct levels of costimulatory and inflammatory signals known to influence T cell differentiation.…”

Section: Introductionmentioning

confidence: 90%

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Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection

Künzli

Reuther

Pinschewer

et al. 2020

Preprint

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A hallmark of the adaptive immune response is the ability of CD4 T cells to differentiate into a variety of pathogen appropriate and specialized effector subsets. A long-standing question in CD4 T cell biology is whether the strength of TCR signals can instruct one Th cell fate over another. The contribution of TCR signal strength to the development of Th1 and T follicular helper (Tfh) cells has been particularly difficult to resolve, with conflicting results reported in a variety of models. Although cumulative TCR signal strength can be modulated by the infection specific environment, whether or not TCR signal strength plays a dominant role in Th1 versus Tfh cell fate decisions across distinct infectious contexts is not known. Here we characterized the differentiation of CD4 TCR transgenic T cells responding to a panel of recombinant wild type or altered peptide ligand lymphocytic choriomeningitis viruses (LCMV) derived from acute and chronic parental strains. We found that while TCR signal strength positively regulates T cell expansion in both infection settings, it exerts opposite and hierarchical effects on the balance of Th1 and Tfh cells generated in response to acute versus persistent infection. The observation that weakly activated T cells, which comprise up to fifty percent of an endogenous CD4 T cell response, support the development of Th1 effectors highlights the possibility that they may resist functional inactivation during chronic infection. We anticipate that the panel of variant ligands and recombinant viruses described herein will be a valuable tool for immunologists investigating a wide range of CD4 T cell responses.

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Section: Introductionmentioning

confidence: 90%

“…and Tfh cell fates is controversial (4)(5)(6)(7)(8)(9)(10)(11)(12). An essential role for TCR signal was implicated in a study assessing the phenotype of progeny derived from individual, TCR transgenic (tg) T cells responding during infection (9).…”

Section: Introductionmentioning

confidence: 99%

Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection

Künzli

Reuther

Pinschewer

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Furthermore, MHCII gene polymorphism has been implicated in establishing or breaking central and peripheral tolerance for Th cells via fine tuning the affinity of pMHCII: TCR interactions and the TCR signal intensity ( Fig. 6c, d, e) [62][63][64][65][66][67][68]. Therefore, MHCII gene polymorphism is associated with the susceptibility or resistance to Th cell-mediated autoimmunity.…”

Section: Clinical Evidencesmentioning

confidence: 99%

MHCII-restricted T helper cells: an emerging trigger for chronic tactile allodynia after nerve injuries

Ding¹,

Luo²,

Qi³

2020

J Neuroinflammation

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Nerve injury-induced chronic pain has been an urgent problem for both public health and clinical practice. While transition to chronic pain is not an inevitable consequence of nerve injuries, the susceptibility/resilience factors and mechanisms for chronic neuropathic pain after nerve injuries still remain unknown. Current preclinical and clinical studies, with certain notable limitations, have shown that major histocompatibility complex class II-restricted T helper (Th) cells is an important trigger for nerve injury-induced chronic tactile allodynia, one of the most prevalent and intractable clinical symptoms of neuropathic pain. Moreover, the precise pathogenic neuroimmune interfaces for Th cells remain controversial, not to mention the detailed pathogenic mechanisms. In this review, depending on the biology of Th cells in a neuroimmunological perspective, we summarize what is currently known about Th cells as a trigger for chronic tactile allodynia after nerve injuries, with a focus on identifying what inconsistencies are evident. Then, we discuss how an interdisciplinary perspective would improve the understanding of Th cells as a trigger for chronic tactile allodynia after nerve injuries. Finally, we hope that the expected new findings in the near future would translate into new therapeutic strategies via targeting Th cells in the context of precision medicine to either prevent or reverse chronic neuropathic tactile allodynia.

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“…Were this not so, there wouldn't even be ineffective T cell responses to nonself epitopes since at least one of out of many heterogeneous T helper cell responses (Th 1 , Th 2 , Th 17 , Th 22 , Th 9 , etc) would be effective. Moreover, both ineffective T helper responses to nonself and their control by thymic Tregs must be epitope-specific (Usharauli and Kamala, 2018;DiToro et al, 2018;Kotov et al, 2019;Akkaya et al, 2019). In contrast, ineffective, polarizing T helpers must cross-inhibit other types of T helper differentiation in an epitope non-specific manner (otherwise, again, there would not be an ineffective T helper response to begin with).…”

Section: Pathological T Helper Polarization Is Initiated At the Tcr/ementioning

confidence: 99%

Shared TCR epitope cross-reactivity could permit dyads of Foxp3+ regulatory and IL-2-producing T cell precursors to escape thymic purge

Usharauli¹,

Kamala²

2019

Preprint

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The thymus-derived Foxp3+ regulatory T cells (Tregs) represent a unique population of CD4+ T cells responsible for maintaining dominant tolerance to auto-antigens, beneficial microbiota and potential irritants such as allergens on the one hand and efficient but balanced defense against pathogens on the other. How Tregs with high-affinity TCRs for thymically expressed epitopes survive thymic deletion or display such broad functionality is presently unclear. We recently introduced a novel framework dubbed SPIRAL (SPecific ImmunoRegulatory ALgorithm) which suggests that antigen cross-reactivity of thymic Treg repertoire could provide a mechanistic basis for its broad functionality. Here we further develop this model to propose how escape of high-affinity Tregs from thymic purge could be achieved in dyads with high-affinity natural IL-2-producing T cells (IL-2p T cells) sharing TCR epitope cross-reactivity. We believe this interpretation could reconcile contradictions related to Treg ontogeny in the thymus and their role in modulating antigen-specific immune responses.

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TCR Affinity Biases Th Cell Differentiation by Regulating CD25, Eef1e1, and Gbp2

Cited by 54 publications

References 74 publications

Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection

Opposing effects of T cell receptor signal strength on CD4 T cells responding to acute versus chronic viral infection

MHCII-restricted T helper cells: an emerging trigger for chronic tactile allodynia after nerve injuries

Shared TCR epitope cross-reactivity could permit dyads of Foxp3+ regulatory and IL-2-producing T cell precursors to escape thymic purge

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