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Tuberculosis (TB), caused by  Mycobacterium tuberculosis  ( Mtb ), remains a leading cause of death worldwide. A better understanding of the role of CD4 +  and CD8 +  T cells, which are both important to TB protection, is essential to unravel the mechanisms of protection and to identify the key antigens seen by these T cells. We have recently identified a set of  in vivo  expressed  Mtb  genes (IVE-TB) which is expressed during  in vivo  pulmonary infection in mice, and shown that their encoded antigens are potently recognized by polyclonal T cells from tuberculin skin test-positive,  in vitro  ESAT-6/CFP10-responsive individuals. Here we have cloned T cells specific for one of these newly identified  in vivo  expressed  Mtb  (IVE-TB) antigens, Rv2034. T cells were enriched based on the expression of CD154 (CD40L), which represents a new method for selecting antigen-specific (low frequency) T cells independent of their specific function. An Rv2034-specific CD4 +  T-cell clone expressed the Th1 markers T-bet, IFN-γ, TNF-α, IL-2 and the cytotoxicity related markers granzyme B and CD107a as measured by flow cytometry. The clone specifically recognized Rv2034 protein, Rv2034 peptide p81–100 and  Mtb  lysate. Remarkably, while the recognition of the dominant p81–100 epitope was HLA-DR restricted, the T-cell clone also recognized a neighboring epitope (p88–107) in an HLA-DR- as well as HLA-DQ1-restricted fashion. Importantly, the T-cell clone was able to inhibit  Mtb  outgrowth from infected monocytes significantly. The characterization of the polyfunctional and  Mtb  inhibitory T-cell response to IVE-TB Rv2034 at the clonal level provides detailed further insights into the potential of IVE-TB antigens as new vaccine candidate antigens in TB. Our new approach allowed the identification of T-cell subsets that likely play a significant role in controlling  Mtb  infection, and can be applied to the analysis of T-cell responses in patient populations.

plos one

Clonal Analysis of the T-Cell Response to In Vivo Expressed Mycobacterium tuberculosis Protein Rv2034, Using a CD154 Expression Based T-Cell Cloning Method