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Review
. 2016 Jan;183(1):16-29.
doi: 10.1111/cei.12672. Epub 2015 Jul 28.

CD4 T cell differentiation in type 1 diabetes

L S K Walker  1 , M von Herrath  2
Affiliations
Review

CD4 T cell differentiation in type 1 diabetes

L S K Walker et al. Clin Exp Immunol. 2016 Jan.

Abstract

Susceptibility to type 1 diabetes is associated strongly with human leucocyte antigen (HLA) genes, implicating T cells in disease pathogenesis. In humans, CD8 T cells predominantly infiltrate the islets, yet their activation and propagation probably requires CD4 T cell help. CD4 T cells can select from several differentiation fates following activation, and this choice has profound consequences for their subsequent cytokine production and migratory potential. In turn, these features dictate which other immune cell types T cells interact with and influence, thereby determining downstream effector functions. Obtaining an accurate picture of the type of CD4 T cell differentiation associated with a particular immune-mediated disease therefore constitutes an important clue when planning intervention strategies. Early models of T cell differentiation focused on the dichotomy between T helper type 1 (Th1) and Th2 responses, with type 1 diabetes (T1D) being viewed mainly as a Th1-mediated pathology. However, several additional fate choices have emerged in recent years, including Th17 cells and follicular helper T cells. Here we revisit the issue of T cell differentiation in autoimmune diabetes, highlighting new evidence from both mouse models and patient samples. We assess the strengths and the weaknesses of the Th1 paradigm, review the data on interleukin (IL)-17 production in type 1 diabetes and discuss emerging evidence for the roles of IL-21 and follicular helper T cells in this disease setting. A better understanding of the phenotype of CD4 T cells in T1D will undoubtedly inform biomarker development, improve patient stratification and potentially reveal new targets for therapeutic intervention.

Keywords: T cells; cytokine differentiation; diabetes.

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Figures

Figure 1
Figure 1
The original T helper type 1 (Th1)/Th2 paradigm in type 1 diabetes. Type 1 diabetes has been viewed traditionally as a Th1‐mediated pathology, with Th2 cells playing a protective role. The characteristic transcription factors and a selection of surface markers associated with Th1 cells or Th2 cells is shown.
Figure 2
Figure 2
T cell cytokine production in type 1 diabetes (T1D). (a) Many studies have assessed interferon (IFN)‐γ in isolation as a measure of the T helper type 1 (Th1) response. (b) Some studies suggest T cells co‐expressing IFN‐ γ and interleukin (IL)‐17 may be expanded in people with type 1 diabetes [60,71]. (c) IL‐21‐producing T cells in the pancreas in mouse models of diabetes have been shown to co‐express tumour necrosis factor (TNF)‐α and IFN‐γ [106]. IL‐21‐producing T cells are elevated in T1D patients [67,106], and can co‐express TNF‐α and IFN‐γ [106].
Figure 3
Figure 3
Potential effects of interleukin (IL)‐21 on immune cells in type 1 diabetes. IL‐21 is a highly pleiotropic cytokine and could potentially act on several different cell types in the context of type 1 diabetes development (see text for references).
Figure 4
Figure 4
Potential utility of biomarkers arising from a better understanding of the T cell phenotype in type 1 diabetes (T1D). Surface markers and/or secreted products from CD4 T cells can potentially be used to gauge the risk of T1D development, in conjunction with established risk indicators. They may also be used to refine patient stratification, perhaps selecting groups that might be predicted to benefit from a particular immune intervention. Longitudinal studies may reveal whether particular markers can be used to stage the disease process. Phenotypical markers may also be of utility in assessing the efficacy of therapeutic interventions, perhaps in combination with tetramer technology.
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