Introduction
Helper T (Th) lymphocyte subsets are critical components of the adaptive immune system, characterized by distinct molecular profiles, cytokine production, effector functions, and tissue distribution [1]. These subsets arise from the differentiation of CD4+ naïve T cells in the thymus under the influence of antigenic stimulation, intrinsic cytokines, and transcriptional signaling. Well-studied Th subsets include Th1, Th2, Th17, Treg, Th22, and Th9 [2,3]. Th subsets act as central regulators of adaptive immunity, modulating cytotoxic T cell responses, antibody production by B cells, and interactions with innate immune components. Dendritic cell-derived cytokines are pivotal in directing Th subset differentiation [4]. These subsets play dual roles in health and disease: they are essential for host defense against pathogens but also drive immune-mediated pathologies such as infections, inflammatory disorders, autoimmune diseases, allergies, and cancer [2,5,6].

Cytokines dictate Th subset differentiation, and the balance among subsets maintains immune homeostasis. Dysregulation of this equilibrium leads to pathological states [6]. This review explores the functional roles of Th subsets and their clinical implications in disease.

Th Subsets and Their Clinical Associations
Th1/Th2
Th1 and Th2 cells, the earliest described Th subsets, have been extensively studied. Th1 cells mediate cellular immunity by producing interferon-gamma (IFN-γ), which activates phagocytes, enhances antibody-dependent cytotoxicity, and combats intracellular pathogens (e.g., viruses) and tumors. However, Th1-driven inflammation contributes to autoimmune conditions such as autoimmune encephalitis, chronic inflammatory bowel disease, and collagen-induced arthritis [9]. In contrast, Th2 cells promote humoral immunity via interleukin-4 (IL-4), which drives antibody production against extracellular pathogens (e.g., parasites) and mediates allergic responses, transplantation tolerance, and pregnancy-related immune adaptation. Th1 and Th2 mutually inhibit each other to maintain equilibrium under physiological conditions. Pathological imbalances favoring one subset over the other are linked to disease progression.

Clinical Examples:

nChronic hepatitis B (HBV) and cirrhosis exhibit Th1 dominance [10], whereas late-stage HIV/AIDS and occult hepatitis C (HCV) infections show Th2-skewed responses [11,12].

nIn bacterial sepsis, Th2 dominance correlates with rapid clinical deterioration and higher mortality [13].

nIn cancer, robust Th1 responses (IFN-γ production) enhance antitumor immunity by activating NK cells and macrophages, leading to improved prognosis [14].

Th17/Treg
Th17 cells drive proinflammatory responses and are implicated in autoimmune diseases, while regulatory T cells (Tregs) suppress immune activation to maintain self-tolerance. The Th17/Treg balance is critical for immune homeostasis.

Th17: These cells secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-17 to recruit neutrophils and monocytes during fungal or bacterial infections. Elevated Th17 levels are observed in psoriasis, multiple sclerosis, Crohn’s disease, and atopic dermatitis, highlighting their role in autoimmunity [7]. In cancer, Th17’s role is context-dependent, with dual pro- and antitumor effects depending on tumor type [15].
Tregs: These cells promote tumor immune evasion by suppressing effector T cells in the tumor microenvironment. Early-stage tumors exploit local Tregs to inhibit antitumor responses, while systemic Treg expansion in advanced cancers facilitates metastasis. Targeting Tregs to restore antitumor immunity is a promising therapeutic strategy [16].

Clinical Examples:

nCancer patients with Treg dominance exhibit higher recurrence and metastasis rates [17].

nIn bacterial sepsis, reduced Th17 and elevated Treg levels correlate with septic shock progression [18].

Th22/Th9

Th22: These cells produce IL-22, an IL-10 family cytokine that acts on epithelial, hepatic, and pancreatic cells to defend against invasive pathogens. IL-22 exhibits dual roles in diseases: it suppresses inflammation in early stages but exacerbates tissue damage in chronic phases of conditions like rheumatoid arthritis, asthma, and inflammatory bowel disease [19,20]. Th22 and IL-22 are also implicated in tumor immunity, suggesting potential therapeutic targets [21].

Th9: Primarily secreting IL-9, Th9 cells modulate allergic responses, autoimmune disorders, and mast cell survival. IL-9 also influences B cell activity and exhibits context-dependent antitumor effects [22–24].

Conclusion

Under physiological conditions, Th subsets maintain a dynamic equilibrium to ensure immune homeostasis. Disease states—such as infections, inflammation, or cancer—disrupt this balance via antigen-driven cytokine shifts, leading to immune dysregulation and pathology. Restoring subset equilibrium through therapeutic interventions correlates with clinical improvement. Further research into Th subset dynamics across diseases will deepen our understanding of pathogenesis and guide novel treatment strategies.

References

[1] Read KA, Powell MD, Sreekumar BK, et al. In vitro differentiation of effector CD4+ T helper cell subsets. Methods Mol Biol. 2019;1960:75-84.
[2] Zhu J. T Helper cell differentiation, heterogeneity, and plasticity. Cold Spring Harb Perspect Biol. 2018;10(10):a030338.
[3] Morel PA. Differential T-cell receptor signals for T helper cell programming. Immunology. 2018;155(1):63-71.
[4] Schmitt N, Ueno H. Regulation of human helper T cell subset differentiation by cytokines. Curr Opin Immunol. 2015;34:130-136.
[5] Raphael I, Nalawade S, Eagar TN, et al. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74(1):5-17.
[6] Ivanova EA, Orekhov AN. T helper lymphocyte subsets and plasticity in autoimmunity and cancer: an overview. Biomed Res Int. 2015;2015:327470.
[7] Zhang Y, Zhang Y, Gu W, et al. TH1/TH2 cell differentiation and molecular signals. Adv Exp Med Biol. 2014;841:15-44.
[8] Girolomoni G, Strohal R, Puig L, et al. The role of IL-23 and the IL-23/TH17 immune axis in the pathogenesis and treatment of psoriasis. J Eur Acad Dermatol Venereol. 2017;31(10):1616-1626.
[9] Hirahara K, Poholek A, Vahedi G, et al. Mechanisms underlying helper T-cell plasticity: implications for immune-mediated disease. J Allergy Clin Immunol. 2013;131(5):1276-1287.
[10] Li MH, Zhang D, Zhang L, et al. Ratios of T-helper 2 cells to T-helper 1 cells and cytokine levels in patients with hepatitis B. Chin Med J (Engl). 2017;130(15):1810-1815.
[11] Mousa N, Eldars W, Eldegla H, et al. Cytokine profiles and hepatic injury in occult hepatitis C versus chronic hepatitis C virus infection. Int J Immunopathol Pharmacol. 2014;27(1):87-96.
[12] Gorenec L, Zidovec Lepej S, Grgic I, et al. The comparison of Th1, Th2, Th9, Th17 and Th22 cytokine profiles in acute and chronic HIV-1 infection. Microb Pathog. 2016;97:125-130.
[13] Gupta DL, Bhoi S, Mohan T, et al. Coexistence of Th1/Th2 and Th17/Treg imbalances in patients with post traumatic sepsis. Cytokine. 2016;88:214-221.
[14] Vesely MD, Kershaw MH, Schreiber RD, et al. Natural innate and adaptive immunity to cancer. Annu Rev Immunol. 2011;29:235-271.
[15] Chang SH. T helper 17 (Th17) cells and interleukin-17 (IL-17) in cancer. Arch Pharm Res. 2019;42(7):549-559.
[16] Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Sci. 2019;110(7):2080-2089.
[17] Lanca T, Silva-Santos B. The split nature of tumor-infiltrating leukocytes: implications for cancer surveillance and immunotherapy. Oncoimmunology. 2012;1(5):717-725.
[18] Tang MS, Bowcutt R, Leung JM, et al. Integrated analysis of biopsies from inflammatory bowel disease patients identifies SAA1 as a link between mucosal microbes with TH17 and TH22 cells. Inflamm Bowel Dis. 2017;23(9):1544-1554.
[19] Tamasauskiene L, Sitkauskiene B. Role of Th22 and IL-22 in pathogenesis of allergic airway diseases: proinflammatory or anti-inflammatory effect? Pediatr Neonatol. 2018;59(4):339-344.
[20] Jia L, Wu C. The biology and functions of Th22 cells. Adv Exp Med Biol. 2014;841:209-230.
[21] Deng Y, Wang Z, Chang C, et al. Th9 cells and IL-9 in autoimmune disorders: pathogenesis and therapeutic potentials. Hum Immunol. 2017;78(2):120-128.
[22] Koch S, Sopel N, Finotto S. Th9 and other IL-9-producing cells in allergic asthma. Semin Immunopathol. 2017;39(1):55-68.
[23] Chauhan SR, Singhal PG, Sharma U, et al. Th9 cytokines curb cervical cancer progression and immune evasion. Hum Immunol. 2019;80(12):1020-1025.