Inhibitory Receptors and Pathways of Lymphocytes: The Role of PD-1 in Treg Development and Their Involvement in Autoimmunity Onset and Cancer Progression

Abstract

Regulatory T (Treg) cells represent a subpopulation of suppressor CD4+ T cells critically involved in the establishment of peripheral tolerance through the inhibition of effector T (Teff) cells and the suppression of the immune-mediated tissue destruction toward self-antigens. Treg generation, their suppressive properties and also Treg-Teff cell interactions could be modulated at least in part by programmed cell death-1 (PD-1) expression on their surface and through binding between PD-1 and programmed cell death ligand-1 (PD-L1). Defects involving PD-1 and Tregs can lead to the development of pathological conditions, including autoimmune disorders or promote cancer progression by favoring tumor evasion from the host immune response. At the same time, PD-1 and Tregs could represent attractive targets for treatment, as demonstrated by the therapeutic blockade of PD-L1 applied for the management of different cancer conditions in humans. In the present Review, we focus specifically the role of PD-1/PD-L1 on Treg development and activity.

Compromised steady‐state germinal center activity with age in nonhuman primates

“…Next, the expression of FoxP3 and the coinhibitory receptors Lag3 (Huan et al, ) and PD1 (Gianchecchi & Fierabracci, ) (Figure a,b) on CD4 T cells was analyzed. Old NHPs had significantly higher estimated numbers per unit follicular area of FoxP3 hi ( p = .0441) and Lag3 hi ( p = .0001) CD4 cells (Figure c,d) but no significant difference was found in the T‐cell zone (Figure a,b).…”

Treg Heterogeneity, Function, and Homeostasis

“…The PD-1 transmitted signal is crucial to FoxP3 expression and for maintaining Treg homeostasis. The mechanism is not Treg-specific; it is also important for carcinogenesis and tumor evasion of CD8 + and NK lymphocytes (89).…”

Cancer Stem Cells: Devil or Savior—Looking behind the Scenes of Immunotherapy Failure

“…PD-L1, an immune checkpoint protein known to trigger a protumorigenic immunophenotype, was also found to be upregulated on the plasma membrane of melanoma as well as ovarian, breast, colon, and lung CSCs [41][42][43][44]. In particular, PD-L1 binding to its receptor (PD-1) on the T cell plasma membrane inhibits the production of immunostimulating cytokines (i.e., IFN-γ and IL-2) [45,46], dampens the T cell-mediated immune response [47], and promotes the expansion of immunosuppressive regulatory T (T-reg) cells [48].…”

“…immunostimulating cytokines (i.e., IFN-γ and IL-2) [45,46], dampens the T cell-mediated immune response [47], and promotes the expansion of immunosuppressive regulatory T (T-reg) cells [48]. The recent introduction of monoclonal antibodies (mAbs) targeting the PD-1/PD-L1 signaling axis in cancer therapy significantly improved the survival of patients with different advanced and aggressive tumor types, including melanoma, non-small-cell lung cancer, and kidney carcinoma [49].…”