Regulation of T Helper Cell Fate by TCR Signal Strength

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2020 Jun 9

PMID 32508803

Citations 48

Authors

Nayan D Bhattacharyya

Carl G Feng

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

The function of T cells in immune thrombocytopenia.

Bu S, Liu M, Yang L, Lee P, Miller H, Park C Front Immunol. 2025; 16:1499014.

PMID: 40061938 PMC: 11885273. DOI: 10.3389/fimmu.2025.1499014.

Capivasertib enhances chimeric antigen receptor T cell activity in preclinical models of B cell lymphoma.

Hsieh H, Urak R, Clark M, Kwak L, Forman S, Wang X Mol Ther Methods Clin Dev. 2025; 33(1):101421.

PMID: 40008088 PMC: 11850743. DOI: 10.1016/j.omtm.2025.101421.

Langerhans Cells Drive Tfh and B Cell Responses Independent of Canonical Cytokine Signals.

Bouteau A, Qin Z, Zurawski S, Zurawski G, Igyarto B bioRxiv. 2025; .

PMID: 39868337 PMC: 11760737. DOI: 10.1101/2025.01.10.632426.

Metabolism of cancer cells and immune cells in the initiation, progression, and metastasis of cancer.

Jiang M, Fang H, Tian H Theranostics. 2025; 15(1):155-188.

PMID: 39744225 PMC: 11667227. DOI: 10.7150/thno.103376.

CD6 regulates CD4 T follicular helper cell differentiation and humoral immunity during murine coronavirus infection.

Cardani-Boulton A, Lin F, Bergmann C J Virol. 2024; 99(1):e0186424.

PMID: 39679790 PMC: 11784103. DOI: 10.1128/jvi.01864-24.

References

Colombetti S, Benigni F, Basso V, Mondino A . Clonal anergy is maintained independently of T cell proliferation. J Immunol. 2002; 169(11):6178-86. DOI: 10.4049/jimmunol.169.11.6178. View

Skokos D, Shakhar G, Varma R, Waite J, Cameron T, Lindquist R . Peptide-MHC potency governs dynamic interactions between T cells and dendritic cells in lymph nodes. Nat Immunol. 2007; 8(8):835-44. DOI: 10.1038/ni1490. View

Hong J, Persaud S, Horvath S, Allen P, Evavold B, Zhu C . Force-Regulated In Situ TCR-Peptide-Bound MHC Class II Kinetics Determine Functions of CD4+ T Cells. J Immunol. 2015; 195(8):3557-64. PMC: 4592802. DOI: 10.4049/jimmunol.1501407. View

Hayden M, Ghosh S . NF-κB in immunobiology. Cell Res. 2011; 21(2):223-44. PMC: 3193440. DOI: 10.1038/cr.2011.13. View

Ahlers J, Belyakov I, Thomas E, Berzofsky J . High-affinity T helper epitope induces complementary helper and APC polarization, increased CTL, and protection against viral infection. J Clin Invest. 2001; 108(11):1677-85. PMC: 200990. DOI: 10.1172/JCI13463. View

Tubo N, Pagan A, Taylor J, Nelson R, Linehan J, Ertelt J . Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell. 2013; 153(4):785-96. PMC: 3766899. DOI: 10.1016/j.cell.2013.04.007. View

Huang J, Brameshuber M, Zeng X, Xie J, Li Q, Chien Y . A single peptide-major histocompatibility complex ligand triggers digital cytokine secretion in CD4(+) T cells. Immunity. 2013; 39(5):846-57. PMC: 3846396. DOI: 10.1016/j.immuni.2013.08.036. View

Wang J, Reinherz E . The structural basis of αβ T-lineage immune recognition: TCR docking topologies, mechanotransduction, and co-receptor function. Immunol Rev. 2012; 250(1):102-19. PMC: 3694212. DOI: 10.1111/j.1600-065X.2012.01161.x. View

Benson R, MacLeod M, Hale B, Patakas A, Garside P, Brewer J . Antigen presentation kinetics control T cell/dendritic cell interactions and follicular helper T cell generation in vivo. Elife. 2015; 4. PMC: 4558563. DOI: 10.7554/eLife.06994. View

10.

Krishnamoorthy V, Kannanganat S, Maienschein-Cline M, Cook S, Chen J, Bahroos N . The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate. Immunity. 2017; 47(3):481-497.e7. PMC: 5661949. DOI: 10.1016/j.immuni.2017.09.001. View

11.

Stanford S, Rapini N, Bottini N . Regulation of TCR signalling by tyrosine phosphatases: from immune homeostasis to autoimmunity. Immunology. 2012; 137(1):1-19. PMC: 3449242. DOI: 10.1111/j.1365-2567.2012.03591.x. View

12.

Govern C, Paczosa M, Chakraborty A, Huseby E . Fast on-rates allow short dwell time ligands to activate T cells. Proc Natl Acad Sci U S A. 2010; 107(19):8724-9. PMC: 2889346. DOI: 10.1073/pnas.1000966107. View

13.

Boomer J, Green J . An enigmatic tail of CD28 signaling. Cold Spring Harb Perspect Biol. 2010; 2(8):a002436. PMC: 2908766. DOI: 10.1101/cshperspect.a002436. View

14.

Grumont R, Lock P, Mollinari M, Shannon F, Moore A, Gerondakis S . The mitogen-induced increase in T cell size involves PKC and NFAT activation of Rel/NF-kappaB-dependent c-myc expression. Immunity. 2004; 21(1):19-30. DOI: 10.1016/j.immuni.2004.06.004. View

15.

Ismail N, Bretscher P . The Th1/Th2 nature of concurrent immune responses to unrelated antigens can be independent. J Immunol. 1999; 163(9):4842-50. View

16.

Liu B, Chen W, Evavold B, Zhu C . Accumulation of dynamic catch bonds between TCR and agonist peptide-MHC triggers T cell signaling. Cell. 2014; 157(2):357-368. PMC: 4123688. DOI: 10.1016/j.cell.2014.02.053. View

17.

Cheng J, Phong B, Wilson D, Hirsch R, Kane L . Akt fine-tunes NF-κB-dependent gene expression during T cell activation. J Biol Chem. 2011; 286(41):36076-36085. PMC: 3195567. DOI: 10.1074/jbc.M111.259549. View

18.

Rossjohn J, Gras S, Miles J, Turner S, Godfrey D, McCluskey J . T cell antigen receptor recognition of antigen-presenting molecules. Annu Rev Immunol. 2014; 33:169-200. DOI: 10.1146/annurev-immunol-032414-112334. View

19.

Cheng J, Montecalvo A, Kane L . Regulation of NF-κB induction by TCR/CD28. Immunol Res. 2011; 50(2-3):113-7. PMC: 4066383. DOI: 10.1007/s12026-011-8216-z. View

20.

Rees W, Bender J, Teague T, Kedl R, Crawford F, Marrack P . An inverse relationship between T cell receptor affinity and antigen dose during CD4(+) T cell responses in vivo and in vitro. Proc Natl Acad Sci U S A. 1999; 96(17):9781-6. PMC: 22287. DOI: 10.1073/pnas.96.17.9781. View