Reduced interleukin-2 receptor subunit γ expression in Crohn's disease: A potential mechanism for γδ T cell deficiency

Abstract

Crohn’s disease (CD) is a chronic inflammatory disorder characterized by dysregulated immune responses and significant disruption of intestinal immunity. A recent case-control study by Andreu-Ballester et al revealed decreased expression of interleukin (IL)-2 receptor subunit γ (CD132) in CD tissues, a finding that has profound implications for understanding immune dysregulation in CD. CD132, an essential component of the IL-7/IL-2 signaling axis, is critical for γδ T cell survival and function, which are pivotal for maintaining gut integrity and modulating inflammation. Here, we propose that reduced CD132 expression represents a key mechanism underlying γδ T cell deficiencies in CD, contributing to impaired immune surveillance and exacerbated inflammation. This hypothesis integrates emerging evidence from cytokine signaling and immunopathology in CD, offering new insights into its pathogenesis. These findings highlight the therapeutic potential of targeting the IL-7/IL-2 axis to restore immune homeostasis in CD, presenting a novel avenue for future research and intervention.

Key Words: Crohn's disease; Gastrointestinal immunology; Interleukin-2 receptor γ subunit (CD132); Interleukin-7/interleukin-2 signaling pathway; Immune regulation; Immune signaling; T cell apoptosis

Core Tip: Crohn’s disease (CD) is characterized by immune dysregulation, with reduced expression of the interleukin (IL)-2 receptor γ subunit (CD132) playing a pivotal role. CD132 is essential for IL-7/IL-2 signaling, which supports γδ T cell survival and function. Its downregulation impairs immune surveillance, exacerbates γδ T cell deficiency, and contributes to inflammation. This study highlights the therapeutic potential of targeting the IL-7/IL-2 axis to restore immune homeostasis in CD. Future research should explore CD132 modulation as a novel strategy to mitigate γδ T cell dysfunction and improve outcomes for CD patients.

TO THE EDITOR

We read with interest the recent case-control study by Andreu-Ballester et al[1], which explores interleukin (IL)-2 receptor γ subunit (CD132) expression in Crohn’s disease (CD) tissues. The study provides valuable insights into the immunological alterations in CD, particularly concerning γδ T cell deficiency and apoptosis. While the findings are compelling, we would like to highlight a potential underlying mechanism for the observed γδ T cell deficiency - specifically, the role of the IL-7/IL-2 receptor axis and the reduced expression of the CD132[1,2].

Emerging evidence suggests that γδ T cells are crucial for maintaining immune homeostasis within the intestinal mucosa. A increasing body of research has demonstrated that CD patients exhibit significant deficiencies in γδ T cell populations, contributing to a compromised immune response[3]. As a specialized subset of T cells, γδ T cells play a vital role in intestinal immunity by rapidly responding to stress-induced antigens and promoting tissue repair. Through the production of cytokines like IL-17 and IFN-γ, they help maintain epithelial barrier integrity and facilitate pathogen clearance[4].

CD is characterized by epithelial barrier defects, microbial dysbiosis, and immune dysregulation driven in part by overactive pro-inflammatory pathways (e.g., TNF-α, IL-23/IL-17) and immune cell imbalances. Dysfunction of γδ T cells, potentially linked to CD132 downregulation, may further compromise gut integrity and exacerbate disease pathology[5]. The findings of the Andreu-Ballester et al[1] aligns with these observations, demonstrating decreased γδ T cell populations in peripheral blood and increased apoptosis among both αβ and γδ T cell subsets in CD patients. These results underscore a broader immune dysregulation in CD that warrants further investigation.

Notably, the study[1] also reports elevated IL-7 expression in CD tissues, a cytokine crucial for T cells survival and homeostasis, including γδ T cells. However, while IL-7 levels were higher in CD patients compared to healthy controls, no corresponding increase in serum IL-7 levels was observed, suggesting a potential disruption in autocrine/paracrine signaling. This discrepancy raises the possibility of an impaired IL-7 signaling response, which may contribute to the observed γδ T cell deficiency[1].

One of the most striking findings in the study was the significant reduction in the expression of the CD132 in CD tissues. CD132, a critical receptor subunit, is essential for the proper function of several cytokine receptors, including those for IL-7, IL-2, IL-15, IL-9, and IL-21. It plays a vital role in T cell survival, proliferation, and differentiation. Its downregulation in CD tissues could impair the effective response of γδ T cells to IL-7, exacerbating deficiencies in this crucial immune subset. Furthermore, reduced CD132 expression may hinder γδ T cells’ ability to respond to other cytokines, further compromising immune defense and contributing to the chronic inflammation characteristic of CD.

The observed decrease in CD132 expression suggests a potential mechanism of immune dysregulation in CD. Impaired CD132 expression may create an imbalance in IL-17 signaling, leading to an adequate immune response. Since CD132 is integral to cytokine receptors involved in intestinal immunity, its downregulation could further disrupt immune surveillance and exacerbate disease progression. CD132, also known as common γ-chain, is essential for IL-7-mediated activation of pathways like JAK-STAT and PI3K-AKT, which support γδ T cell survival, proliferation, and function. Its downregulation could impair immune surveillance and tissue repair in the intestinal mucosa. As CD132 is shared by the receptors of IL-2 and IL-15, its decrease may further impair cytokine signaling, worsening immune dysregulation in CD. Future research should explore the causes of CD132 downregulation, its effects on γδ T cells, and therapeutic strategies to restore immune homeostasis.

These findings underscore the potential of therapeutic strategies aimed at restoring CD132 function or enhancing IL-7 receptor signaling. For example, IL-7 receptor agonists could be explored to compensate for reduced signaling in γδ T cells. Additionally, CD132-specific monoclonal antibodies designed to stabilize its expression or function might offer a novel therapeutic avenue. Early-phase clinical trials could evaluate the safety and efficacy of these approaches in improving γδ T cell function and modulating immune responses in CD patients.

Andreu-Ballester et al[1] used quantitative PCR and immunohistochemistry to evaluate CD132 expression, offering key insights into molecular changes. However, a small cohort size limits generalizability, as patient variability could affect results. While PCR detects gene expression, it overlooks post-transcriptional regulation and protein functionality, highlighting the need for complementary techniques like flow cytometry or western blotting. The study also did not examine downstream pathways (e.g., JAK-STAT, PI3K-AKT) critical for T cell function. Additionally, its cross-sectional design limits causal inferences. Longitudinal studies could better link CD132 expression to disease progression. Despite these gaps, the findings underscore CD132's role in immune dysregulation and its potential as a therapeutic target[1].

Future research should also investigate the interplay between CD132 expression and other cytokine signaling pathways, such as IL-2 and IL-15, to better understand their collective impact on immune regulation in CD. Such studies could inform the design of targeted interventions that correct γδ T cell deficiencies and improve outcomes for patients with CD. Additionally, while CD132 plays a key role in cytokine signaling (e.g., IL-2, IL-7, IL-15), the precise relationship between its expression levels and γδ T cell function has not been thoroughly explored. Most existing studies focus on overall T cell populations, and dedicated research on γδ T cell subsets in CD is sparse. Furthermore, there is a lack of in vivo studies that evaluate the therapeutic efficacy of targeting CD132 or modulating the IL-7/IL-2 receptor axis in animal models or clinical settings. Addressing these gaps is crucial for advancing our understanding of immune dysregulation in CD and for developing targeted therapeutic strategies.

In conclusion, the study by Andreu-Ballester et al[1] provides valuable insights into the immunological alterations in CD, particularly the role of γδ T cell deficiencies. We propose that the reduced expression of CD132 may represent a critical mechanism underlying this deficiency. Further investigation into the role of IL-7 receptor signaling and the therapeutic potential of targeting CD132 is warranted to advance our understanding of immune dysregulation in CD and to develop innovative treatment strategies.