Abstract
ObjectiveInfection by MTB or exposure to MTB constituents is associated with intense microbial stimulation of the immune system, through both antigenic and TLR components, and induction of a milieu that is rich in pro-inflammatory/anti-inflammatory cytokines. Here, we addressed the basis of induced regulatory T-cell (iT-reg) expansion in response to MTB stimulation, in the absence of prior T cell antigen responsiveness.MethodsPBMC from HIV-1 un-infected TST negative and TST positive control subjects were stimulated by virulent MTB H37Rv lysate (L), a French press preparation of MTB that includes all bacterial components. Phenotype of MTB H37RvL induced iT-reg was assessed using immunostaining and flow cytometry. Functional capacity of iT-reg was assessed using 3H-Thymidine incorporation and IFNγ production of non-adherent T cells (NAC) in the presence or absence of iT-reg in corresponding culture supernatants in response to TCR stimulation. Realtime PCR was used to assess IDO and FoxP3 mRNA expression.ResultsThe capacity of MTB H37RvL to induce CD4+CD25hi+ Foxp3+ T-cells in PBMC from TST negative subjects was robust (p<0.001), and in fact comparable to induction of iT-reg in PBMC from TST positive subjects. MTB-induced CD4+CD25hi+ T-reg were TGFβ positive (p<0.05). Further, MTB H37RvL induced CD4+CD25hi+ Foxp3+ iT-reg suppressed 3H-Thymidine incorporation and IFNγ production of non-adherent T cells (NAC) in response to TCR stimulation. MTB H37RvL induction of iT-reg was significantly stronger (p<0.01) than that by TLR-2, TLR-4, TLR-9 ligands, or combination of all TLR ligands. MTB H37RvL inducted indoleamine 2,3-dideoxygenase (IDO) mRNA expression in monocytes (p<0.001), and co-culture with the IDO inhibitor, D-1MT, decreased frequencies of T-reg (p<0.05). Inhibition of TGFβ by siRNA reduced Foxp3 mRNA expression in CD4 T cells (p<0.05).ConclusionTherefore, MTB and its components expand functional iT-reg in human mononuclear cells from MTB non-sensitized subjects. Also, MTB-induced iT-reg expansion depends on mononuclear phagocyte expression of both TGFβ and IDO.
Highlights
Expansion of Foxp3+CD4 T cells with regulatory function (T-reg) associated with infections and malignancies have been shown to be primarily due to T cell immune responses to microbial or tumor antigens
M. tuberculosis (MTB)-induced iT-reg expansion depends on mononuclear phagocyte expression of both TGFβ and IDO
T-regs are characterized by expression of high surface levels of CD25, intracellular expression of Foxp3, and suppression of T-cell responses to TCR stimulation [18]
Summary
Expansion of Foxp3+CD4 T cells with regulatory function (T-reg) associated with infections and malignancies have been shown to be primarily due to T cell immune responses to microbial or tumor antigens. A role for induced (i) T-reg in limiting immunogenicity of novel antigens subsequent to immunization or infection in humans has been examined, remains controversial [2,3]. Mononuclear cells recruited to sites of M. tuberculosis (MTB) infection or novel MTB antigens, are exposed to MTB Toll-like receptor (TLR) ligands. MTB is rich in TLR2 ligands [4,5], and a role for TLR2 ligand in expansion of T-reg has been previously shown [6]. The role of TLR2 and other TLR ligands of MTB in accumulation of iT-reg have not been fully examined
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