First Evidence That Th22 Cells May Contribute To the Pathogenesis of Graves’ Disease

Th22 Cells Pathogenesis Graves Disease
Th22 Cells – Pathogenesis of Graves’ Disease

The many immune mechanisms involved in the onset and development of autoimmune diseases make their pathophysiology heterogeneous and complex. Among them, CD4+ T cells play a central role in the regulation of immunity and in maintaining a balance between pro- and anti- inflammatory responses (1). After the interaction with MHC-II molecules expressed on the surface of antigen-presenting cells, naïve CD4+ T cells differentiate into specific subtypes depending mainly on the cytokine milieu of the microenvironment (2, 3). These several subsets of CD4+ T cells shape the adaptive immune responses. For many years CD4+ effector T cells were assigned to either the T helper (Th)1 or Th2 subtypes. Each subtype has its own distinct cytokines, transcription factors, functions, and most phenomena related to adaptive immunity were explained by the Th1/Th2 cell balance. Th1 cells drive cell-mediated immune responses to fight intracellular pathogens and Th2 cells essentially eliminate extracellular antigens, support humoral immunity and are involved in allergic reactions (3, 4).

As Peng and colleagues describe in their study, Graves’ disease (GD) was defined as a predominant Th2 autoimmune condition associated with the production of stimulating anti-TSH receptor antibodies (TSAb) which leads to overstimulation of the thyroid glands. In the 90s, the CD4+ regulatory T cells (Tregs) opened a new perspective: due to their immunosuppressive function, they were shown to play a central role in the control of several autoimmune disorders including autoimmune thyroid diseases (5, 6, 7).

Since the beginning of the new millennium, advances in the field of CD4+ T cells immunobiology brought us new Th subsets such as the Th17 and the recently described Th22 subtype shown in the Peng et al. study. Th17 cells, producing IL-17A, IL-17F, IL-21, and IL-22, are important effector cells for extracellular pathogens including bacteria and fungi, and participate in inflammation and autoimmune diseases (8, 9).

Although IL-22 was originally described as a cytokine characteristic of fully differentiated Th17 cells, it was recently demonstrated to be produced by a distinct subset of human skin-homing memory T cells, namely Th22 (10). These cells were shown to participate in skin homeostasis and pathology (10), but lately it has been assigned their role in inflammatory and autoimmune diseases as well (11, 12). The role of Th17 cells in the pathogenesis of GD remains uncertain and Peng et al. were the first to demonstrate the participation of Th22 in this pathology. It is worth noting that today the role of Th22 cell in autoimmune diseases has become a hot issue in immunology due to its potential as a targeting tool for therapeutic intervention.

In their study Peng and coworkers bring us interesting results on the role of Th22 on the onset of Graves’ disease autoimmunity. In fact, the authors showed that GD patients have higher percentages of Th22 and Th17 cells, accompanied by higher concentrations of plasma IL-22 and IL-17, respectively, when compared to healthy controls. Also, these results positively correlate with serum concentrations of TSAb in Graves’ hyperthyroid patients, thus indicating that increased numbers of Th22 and Th17 cells are associated with the development of GD in the studied population.

There are several points to highlight from the study by Peng et al. First, the authors clearly differentiate Th22 from the Th17 cell subtype by multicolor staining of CD4+ cells from GD patients´ peripheral blood mononuclear cells (PBMC). In addition, the simultaneous expression of both cytokines by the same human T cell is rather an exception (13) and GD patients seem not to be the exception: the authors showed that the percentage of cells producing both IL-17A and IL-22 was very low (less than 0.4%).

Second, they confirm the contribution of Th17 in the pathogenesis of GD, strengthening the fact that its involvement would probably rely on genetic factors and thus explain some controversial results in the literature. This reinforces the necessity to reproduce similar studies in populations with different genetic background.

Third, besides being the first to demonstrate a role for Th22 in GD, the authors also support the notion that these cells can also regulate organ-specific autoimmunity in humans in addition to their involvement in epidermal immunity.

Finally, Peng et al. were critical when discussing their results and clearly presented the limitations of their study. They used a small sample size at the onset of the disease, and they did not perform any functional analysis of the different T cell subsets. The goal would be to study the immune responses to thyroid antigens of specific T cell clones isolated from patients with GD. T cell clones reactive to human recombinant TSH-receptor extracellular domain and/or its peptides were already demonstrated (14-16).

Nevertheless, a very recent study by Song et al. (16) confirms Peng and coworker´s results. In fact, they show that GD patients have a higher proportion of Th22 cells and IL-22 serum levels than healthy controls. This discrepancy was not observed in patients with Hashimoto’s thyroiditis, another autoimmune disorder that leads to hypothyroidism. This clearly points out the important role that Th22 cells play in the pathogenesis of GD and open an interesting question whether this is related to the high levels of circulating thyroid hormones present in this pathology. The increment in T lymphocyte number and cytokine secretion by hyperthyroid, but not hypothyroid conditions was already demonstrated (17).

So, studies like this of Peng et al. should be encouraged to improve the knowledge and understanding of the intricate and complex interplay of T cell subsets that lead to GD and other autoimmune thyroid disorders.

Author(s) Affiliation

Graciela Cremaschi, PhD; Department of Neuroimmunomodulation and Molecular Oncology, Institute for Biomedical Research (BIOMED), Catholic University of Argentina (UCA), National Research Council of Argentina (CONICET), Buenos Aries, Argentina; email:


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    on the study by Di Peng et al., PLoS One. 2013 Jul 11;8(7):e68446
    A High Frequency of Circulating Th22 and Th17 Cells in Patients with New Onset Graves’ Disease

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