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T helper subsets: Differentiation and role in disease

Zuhair K Ballas, MD
Section Editor
Luigi D Notarangelo, MD
Deputy Editor
Elizabeth TePas, MD, MS


The division of T helper responses along a T helper type 1 (Th1) or a T helper type 2 (Th2) pathway has aided in the understanding of numerous basic immunologic pathways and diseases. As more knowledge is gained, it is apparent that these subsets represent the tip of the iceberg in the multiple checks and balances that are characteristic of the immune system. After the discovery of the Th1/Th2 dichotomy, most research was dedicated to understanding their cytokine polarization. The emphasis then shifted to examining the signals required for Th1/Th2 differentiation. The focus then shifted yet again to examining the role of dendritic cell (DC) subsets, rediscovered regulatory T cells, and newly discovered T helper type 17 (Th17) cells in modulating immune responses. The next wave of research in this area may yield insight not only into the modulation of T helper subsets but into potential therapeutic manipulation of these subsets in human disease.

There is detailed understanding of the modulation of T helper cell responses in mice. However, data in humans are less complete, and the exact characteristics of Th17 cells and T regulatory (Treg) cells are still being determined. This topic will focus on human immunology, using murine studies only to clarify a point, and will elucidate the known characteristics of these subsets, their differentiation, and their involvement in various diseases. Other details of cellular immunity are discussed separately. (See "Normal B and T lymphocyte development" and "The adaptive cellular immune response".)


Categorization — T cells can be categorized based upon cell surface expression of either cluster of differentiation 4 (CD4) or CD8. CD4+ cells recognize antigen presented in the context of class II major histocompatibility complex (MHC), while CD8+ cells recognize antigen presented in the context of class I MHC.

CD4+ T helper subsets include T helper type 1 (Th1), T helper type 2 (Th2), and T helper type 17 (Th17) cells (figure 1 and table 1) [1]. There is evidence that each of these subsets is involved in the defense against a certain subset of micro-organisms. Th1 are pivotal in defense against intracellular micro-organisms in general and mycobacteria in particular. Patients with mutations in the interferon (IFN)-gamma receptor or interleukin (IL)-12 receptor present with recurrent infections with mycobacteria and Salmonella. Th2 cells are integral in expelling parasitic infestations. Th17 seem to play a significant role in defense against extracellular bacteria and some fungi. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

Th1 and Th17 cells play major roles in autoimmunity, whereas Th2 cells are the hallmark of atopic disease. T regulatory (Treg) cells represent a major subset of CD4+ T cells that may be involved in regulating and attenuating the activity of the three T helper subsets.


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