T Lymphocytes: Helpers


Helper T lymphocytes (TH) are major histocompatibility complex (MHC) class II restricted CD4+ T cells that can be divided into several subsets depending on their cytokine releasing patterns: T‐helper 1 (TH1), TH2, TH17, T‐follicular helper (TFH), forkhead box P3+ regulatory T (Treg) cells and the recently described TH9 and TH22 cells and others. TH1 cells activate infected macrophages for the destruction of intracellular pathogens. TH2 and TFH cells provide help to B cells for antibody production. TH17 cells enhance neutrophil response for extracellular pathogens. Treg cells actively suppress immune reactions and help prevent the development of autoimmunity during immune response. It was initially thought that each TH subset retained a stable phenotype with a distinct lineage and played a distinct role in host defense and autoimmunity. Considerable overlap and flexibility of cytokine production by CD4+ T cells is challenging earlier concepts.

Key Concepts:

  • Helper T lymphocytes (TH) are MHC class II restricted CD4+ T cells that can be divided into several subsets of cytokine releasing patterns: T‐helper 1 (TH1), T‐helper 2 (TH2), T‐helper 17 (TH17), regulatory T (Treg), T‐follicular helper (TFH) and others.

  • TH cell subsets express a distinct set of genes that encode hallmark cytokines and unique transcription factors.

  • IFN‐γ, IL‐4, IL‐17, IL‐10/TGF‐β and IL‐21 are the representative cytokines of TH1, TH2, TH17, Treg and TFH cells, respectively, and are often used as subtype markers.

  • TH1 cells play an important role in cellular immune functions such as delayed‐type hypersensitivity or defense against intracellular organisms.

  • TH2 cells enhance antibody production by B cells.

  • TH17 cells are potent inducers of tissue inflammation in autoimmune diseases and confer protection against extracellular bacterial and fungal pathogens.

  • Treg cells consist of a heterogeneous class of cells that suppress T‐cell activity and help prevent the development of autoimmunity during immune response.

  • TFH cells regulate the step‐wise development of antigen‐specific B cell immunity in B cell follicles of lymphoid tissues.

Keywords: MHC class II; CD4; T‐helper 1; T‐helper 2; T‐helper 17; regulatory T; T‐follicular helper; antibody production

Figure 1.

The classical view of TH cell differentiation. The progeny of antigen experienced CD4+ T cells exposed to specific pathogen‐associated signals, especially cytokines, can develop into T‐helper 1 (TH1), T‐helper 2 (TH2), T‐helper 17 (TH17), regulatory T (Treg), and follicular helper T (TFH) effector cells that can migrate to appropriate tissues. Master regulators and STAT family members collaborate in T cell differentiation and expansion: T‐bet and STAT4 for TH1, GATA3 and STAT5 for TH2, RORγt and STAT3 for TH17, forkhead box P3 (Foxp3) and STAT5 for iTreg, and Bcl6 and STAT3 for TFH. Other transcription factors are either secondary to master regulators and STAT proteins or responsible for the induction of master regulators. Polarised T cells produce different sets of cytokines, and TH1, TH2, TH17, Treg and TFH cells cross‐regulate each other by the cytokines they produce. TH1 cells produce cytokines that activate macrophages, enabling them to destroy intracellular microorganisms more efficiently. TH2 cells produce cytokines that recruit and activate eosinophils, mast cells and basophils and promote barrier immunity at mucosal surfaces. TH17 cells produce IL‐17 family cytokines that induce local epithelial cells to secret chemokines that recruit neutrophils to sites of infection. TFH cells, a subset localised in B cell follicles, produce IFN‐γ that activates B cells to produce strongly opsonising antibodies that belong to certain IgG subclasses. TFH cells also produce IL‐4, driving B cells to differentiate and produce immunoglobulins of other types, especially IgE. Treg cells are a heterogeneous class of cells that suppress T cell activity and help prevent the development of autoimmunity during immune responses. APC, antigen‐presenting cell; CTLA‐4, cytotoxic T–lymphocyte antigen 4; ICOS, inducible T‐cell co‐stimulator; IFN‐γ, interferon‐γ; IL, interleukin; and TGF‐β, transforming growth factor β.

Figure 2.

Diversity and plasticity of TH Cells. Recent studies of TH cells have revealed flexibility in cytokine production, and there are now many examples of plasticity of the TH phenotype. CD4+ T cells can shift their profile of cytokine production and can express more than one master regulator. This schema may support the idea that elements of both terminal differentiation in the case of cytokine genes and plasticity in the case of master regulators genes can coexist within the same TH cell subset. Understanding how to control the stability and plasticity of TH cells will have important therapeutic applications for infection and autoimmunity.

Figure 3. T–B interaction: T cell help to B cells. (a) TH cells recognise processed antigen peptides and are activated. The specific interaction of an antigen‐binding B cell with an armed TH cell leads to the expression of the B cell stimulatory molecule CD40 ligand on the TH cell surface and to the secretion of B cell stimulatory cytokines IL‐4, IL‐5, IL‐6, or IL‐21 that drive the proliferation and differentiation of the B cells into antibody‐secreting plasma cells. Alternatively, an activated B cell can become a memory cell. (b) Many surface molecules are involved in T cell–B cell interaction. The first event is the T cell receptor (TCR) and CD4 engagement of the peptide–MHC complex. This event leads to expression of CD40L on T cells, after which CD40/CD40L interaction causes upregulation of B7 co‐stimulatory ligands on antigen‐presenting cells (APC). The CD40 signal is critical for activating B cells. Signals from TCRs (CD40L) and CD28 activate T cells. CD2 on T cells and MHC on B cells can potentially also serve as co‐stimulatory molecules as well as strengthen adhesion interactions. The B cell stimulatory cytokines IL‐4, IL‐5, IL‐6 or IL‐21 are released at the point of contact, and drive the proliferation and differentiation of the B cells into antibody‐secreting plasma cells.
Figure 4.

Activation of macrophages. Helper T cells produce macrophage‐activating factors such as IFN‐γ and upregulate CD40 ligand (CD40L), followed by recognition of bacterial peptides‐MHC class II on infected macrophages. GM–CSF, granulocyte‐macrophage colony‐stimulating factor; IFN‐γ, interferon‐γ; and TNF‐α, tumor necrosis factor‐α.

Figure 5.

Models of helper functions of CD4+ T cells for CD8+ cytotoxic T cell responses.



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Further Reading

Awasthi A, Murugaiyan G and Kuchroo VK (2008) Interplay between effector Th17 and regulatory T cells. Journal of Clinical Immunology 28: 660–670.

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Sallusto F, Lanzavecchia A and Mackay CR (1998) Chemokines and chemokine receptors in T‐cell priming and Th1/Th2‐mediated responses. Immunology Today 19: 568–574.

Yamane H and Paul WE (2012) Cytokines of the gamma(c) family control CD4+ T cell differentiation and function. Nature Immunology 13: 1037–1044.

Zhu J, Yamane H and Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annual Review of Immunology 28: 445–489.

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Kawachi, Izumi, and Kondo, Takayuki(Sep 2013) T Lymphocytes: Helpers. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001224.pub3]