Programmed Death 1 and Cytokine Inducible SH2-Containing Protein Dependent Expansion of Regulatory T Cells Upon Stimulation With Mycobacterium tuberculosis

Abstract

We previously found that CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) expand in response to Mycobacterium tuberculosis infection in individuals who are healthy tuberculin reactors, but not in tuberculin-negative individuals. We also found that the M. tuberculosis mannose-capped lipoarabinomannan and prostaglandin E2 produced by monocytes are involved in Treg expansion. In this study, we found that Tregs expanded from CD4(+)CCR4(+) cells but not from CCR4(-) cells. However, introduction of CCR4 small interfering RNA (siRNA) into CD4(+) cells only marginally reduced expansion of Tregs. Using siRNA and neutralizing antibodies, we found that expansion of Tregs by M. tuberculosis required expression of programmed death1 (PD-1) and expression of the signaling molecule, cytokine inducible SH2-containing protein (CISH). Anti-PD-1 siRNA inhibited expression of CISH by expanded Tregs. M. tuberculosis-expanded Tregs produced transforming growth factor β and interleukin 10 and reduced the frequency of interferon γ-producing autologous CD8(+) cells. We conclude that M. tuberculosis infection induces development of Tregs from CCR4(+) cells through a process that depends on PD-1and CISH.

PD-1 Upregulated on Regulatory T Cells during Chronic Virus Infection Enhances the Suppression of CD8+ T Cell Immune Response via the Interaction with PD-L1 Expressed on CD8+ T Cells

“…T reg cells also upregulate PD-1 expression on their surfaces during chronic viral infection (20). PD-1:PD-L1 interaction has a critical role in promoting the conversion of conventional T cells into T reg cells and maintaining them (21)(22)(23). However, whether PD-1 expression by T reg cells during chronic infection is associated with the suppression of pathogen-specific T cell immune response remains unknown (24)(25)(26).…”

Development of Virus-Specific CD4 + and CD8 + Regulatory T Cells Induced by Human Herpesvirus 6 Infection

“…Antigen-presenting cells, such as DCs, are essential for the expansion of Treg cells through costimulatory molecules B7 and ICOS and soluble factors, including TGF-␤ and prostaglandin E2 (PGE2). Recent studies have shown that Treg cells expand in response to Mycobacterium tuberculosis through mechanisms dependent on ManLAM, PGE2, PD-1, CISH, and PD-L1 (48)(49)(50).…”

Intravenous immunoglobulin expands regulatory T cells via induction of cyclooxygenase-2–dependent prostaglandin E2 in human dendritic cells

“…[33][34][35][36]46 The interaction of PD-L1 and 2 with PD-1, the members of CD28/B7 family, has a critical role in balancing the T-cell tolerance through inhibiting the activation of effector cells while promoting the generation and expansion of Tregs. 33,34 Pathogens such as Mycobacterium can hijack the immune system by activating the PD-L-PD-1 pathway and thus enhancing the Tregs and preventing the protective immune responses.…”