Regulation of the Interleukin (IL)-12R β2 Subunit Expression in Developing T Helper 1 (Th1) and Th2 Cells

By S. Szabo, A. Dighe, U. Gubler, K. Murphy. 1997

The developmental commitment to a T helper 1 (Th1)- or Th2-type response can significantly influence host immunity to pathogens. Extinction of the IL-12 signaling pathway during early Th2 development provides a mechanism that allows stable phenotype commitment. In this report we demonstrate that extinction of IL-12 signaling in early Th2 cells results from a selective loss of IL-12 receptor (IL-12R) β2 subunit expression. To determine the basis for this selective loss, we examined IL-12R β2 subunit expression during Th cell development in response to T cell treatment with different cytokines. IL-12R β2 is not expressed by naive resting CD4+ T cells, but is induced upon antigen activation through the T cell receptor. Importantly, IL-4 and IFN-γ were found to significantly modify IL-12 receptor β2 expression after T cell activation. IL-4 inhibited IL-12R β2 expression leading to the loss of IL-12 signaling, providing an important point of regulation to promote commitment to the Th2 pathway. IFN-γ treatment of early developing Th2 cells maintained IL-12R β2 expression and restored the ability of these cells to functionally respond to IL-12, but did not directly inhibit IL-4 or induce IFN-γ production. Thus, IFN-γ may prevent early Th cells from premature commitment to the Th2 pathway. Controlling the expression of the IL-12R β2 subunit could be an important therapeutic target for the redirection of ongoing Th cell responses.

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Citations in the corpus

Cytokines in clinical cancer immunotherapy (2018, background): “The β1 subunit is constitutively expressed on immune cells, whereas the β2 subunit is upregulated in T cells and NK cells upon activation.(73) IL-12R activation results in the recruitment of the kinases Janus kinase (JAK2) and Tyk2 and subsequent phosphorylation of signal Producer cell”
Stat4 Regulates Multiple Components of IFN-γ-Inducing Signaling Pathways1 (2000, background): “IL-18R and IL-12R b2 are expressed on Th1, but not on Th2, cells (23, 24, 30).”
Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming (2004, background): “We therefore considered that the NK cells recruited might enhance T H 1 polarization in vivo by providing IFN-γ, which is known to increase both the production of IL-12 by DCs and the expression of T-bet on activated T cell”
Decision making in the immune system: The lineage decisions of helper T cells (2002, unknown): “and that T H 1 cells selectively express a signalling chain of the IL-12 recepto”
Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy (2019, unknown): “Furthermore, IL-2 up-regulates the expression of IL-12 receptor subunit  (34), and IL-12 sustains surface expression of IL-2 receptor CD25 (35).”
IL-18–stimulated GADD45β required in cytokine-induced, but not TCR-induced, IFN-γ production (2001, background): “IL-12 and IL-18 receptors are not expressed by naive CD4 + T cells but are selectively induced during T H 1, but not T H 2, developmen”
Plasticity of CD4+ T cell lineage differentiation. (2009, background): “The Th2 cell cytokine IL-4 appears to repress IL-12 signaling through inhibition of IL-12Rb2 expression, thus antagonizing Th1 cell differentiation (Szabo et al., 1997).”
Role of IFN-γ in Th1 Differentiation: IFN-γ Regulates IL-18Rα Expression by Preventing the Negative Effects of IL-4 and by Inducing/Maintaining IL-12 Receptor β2 Expression (2002, background): “Although high levels of expression of IL-18R and IL-12R 2 have been proposed as markers for Th1 cells (2, 4, 28), our studies have also demonstrated that a rather poor correlation exists between the levels of expression of these receptors and the Th1 differentiation status of CD4 T cells.”
Review: Environmental exposure to mercury and its toxicopathologic implications for public health (2003, background): “They have receptors for IL-12R on their membrane surfaces; and they promote cellular immune responses (Kono et al., 1998; Szabo et al., 1997).”