Abstract

The Notch signaling pathway plays multiple roles in driving T-cell fate decisions, proliferation, and aberrant growth. NF-κB is a cell-context key player interconnected with Notch signaling either in physiological or in pathological conditions. This review focuses on how the multilayered crosstalk between different Notches and NF-κB subunits may converge on Foxp3 gene regulation and orchestrate CD4+ regulatory T (Treg) cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a pivotal role in the inhibition of antitumor immune responses, possibly promoting tumor growth. A future challenge is represented by further dissection of both Notch and NF-κB pathways and consequences of their intersection in tumor-associated Treg biology. This may shed light on the molecular mechanisms regulating Treg cell expansion and migration to peripheral lymphoid organs thought to facilitate tumor development and still to be explored. In so doing, new opportunities for combined and/or more selective therapeutic approaches to improve anticancer immunity may be found.

Highlights

  • Regulatory T (Treg) cells are a heterogeneous population of T lymphocytes

  • PKCθ is involved in Treg cells (Tregs) cell differentiation in vivo, but it is dispensable for Treg-mediated suppression [48]; the balance between the positive (PKCθ) and/or negative

  • The increased number of Tregs within peripheral blood, lymphoid tissue, and the tumor microenvironment is frequently associated with poor prognosis in several cancers

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Summary

Introduction

Regulatory T (Treg) cells are a heterogeneous population of T lymphocytes. Human and mouse Tregs act as gate-keepers of multiple immune reactions, suppressing unwanted immune responses such as autoimmunity, allergy, or transplant rejection [1,2,3]. Murray et al genetically manipulated the NIK expression in mice and demonstrated that the NIK deletion in T cells impairs the maintenance of peripheral Foxp3+ Tregs, suggesting a Tregs intrinsic function for the noncanonical pathway [35]. The lineage-specific constitutive activation of NIK in Treg cells induces an alteration of their functions and gene signature (Gitr+CD25+Foxp3+), leading to the development of an autoimmune syndrome [36].

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