It is generally believed that CD4+CD25+Foxp3+ T-cells (Tregs) inhibit effective immunity to microbial pathogens. In humans, we and others have found increased numbers of CD4+Foxp3+ T-cells in TB patients. We also found that in persons with latent tuberculosis infection (LTBI), Tregs expand in response to Mycobacterium. tuberculosis (Mtb), produce TGF-? and IL-10 and inhibit IFN-? production by CD4+ and CD8+ cells, suggesting that they may limit tissue inflammation and destruction. However, in humans, some activated T-cells express Foxp3 transiently and these cells lack classical regulatory function. Recently we made a surprising observation that a subpopulation of CD4+CD25+Foxp3+ cells from persons with LTBI inhibits growth of M.tb in human monocyte-derived macrophages (MDMs). A soluble factor, Rho GDP dissociation inhibitor (D4GDI), produced by apoptotic CD4+CD25+ Foxp3+D4GDI+ cells is responsible for this inhibition of M.tb growth in human macrophages and in mice. Our study provides the first evidence that a subpopulation of CD4+CD25+Foxp3+ cells enhances immunity to M. tb, and identified a novel IFN-? independent but T-cell dependent mechanism that inhibits M. tb growth in human macrophages. This proposal will determine the role of D4GDI in M.tb infection through the following specific aims.
Aim 1. Determine the mechanisms by which D4GDI inhibit mycobacterial growth.
Aim 2. Characterize the phenotype and function of D4GDI-producing FoxP3+ cells in LTBI+ individuals and tuberculosis patients.
Aim 3. Determine the relevance of expansion of D4GDI+Foxp3+ cells to progression of LTBI to active TB.
Mycobacterium tuberculosis (M.tb) infects one-third of the world?s population and causes almost 1.2 million deaths per year. Control of M.tb infection requires cooperation of the innate and adaptive immune systems. The proposed studies in the grant application will improve our understanding on the contribution of a soluble factor, Rho GDP dissociation inhibitor (produced by CD4+CD25+Foxp3+ cells) to immunity against M.tb and will facilitate development of more effective vaccines.
| Cheekatla, Satyanarayana Swamy; Tripathi, Deepak; Venkatasubramanian, Sambasivan et al. (2017) IL-21 Receptor Signaling Is Essential for Optimal CD4+ T Cell Function and Control of Mycobacterium tuberculosis Infection in Mice. J Immunol 199:2815-2822 |
