Distribution of Mycobacterium tuberculosis-specific CD4+ T cells within distinct human memory subsets
Research area: Cellular Immunology
Group leaders: Federica Sallusto
- Federico Mele, Research Assistant
Status: In progress
While several studies have reported the identification of Mycobacterium tuberculosis (MTB) antigens, from abundant or easily purified proteins, a truly genome-wide study to identify antigens is lacking. Another unresolved issue relating to MTB immunity is whether different classes of antigens elicit responses that have the same or diverse functional characteristics. MTB antigens described so far are predominantly secreted MTB proteins, some of which are not essential for bacterial survival. As a result, it was hypothesized that secreted proteins might act as decoy antigens, diverting the immune response from recognizing more relevant MTB proteins. In this study we used HLA class II peptide binding predictions, HLA class II multimers, and the screening of T cell libraries, to perform an unbiased, genome-wide analysis of the CD4 T cell response to MTB in latently infected individuals. We showed that human CD4 T cells specific for MTB are highly focused on three broadly immunodominant antigenic islands, all related to bacterial secretion systems, thus refuting the notion that secreted antigens act as a decoy, since both secreted proteins and proteins comprising the secretion system itself are targeted by a fully functional T cell response. In addition, several novel T cell antigens were identified which can be of potential diagnostic use, or as vaccine antigens. Using the T cell library technique we showed also that MTB-responding T cells were highly enriched in libraries derived from the CCR6+CXCR3+ T cell subset (enriched in Th1 cells), and present at lower frequency in libraries from the CCR6+CXCR3– (enriched in Th17 cells) and the CCR6– subset (containing both Th1 and Th2 cells). This pattern of distribution was remarkable consistent: in all 4 donors analyzed more than 80% of the MTB-reactive memory CD4 T cell response resided in the CXCR3+CCR6+ subset. We are currently determining the TCR repertoire diversity of MTB-specific T cells in different memory subsets in by deep sequencing in order to define the origin and lineage relationship of these phenotypically and functionally distinct T cell populations.
This work is shared between IRB and La Jolla Institute for Allergy and Immunology, La Jolla, California (US), and was done together with Cecilia S. Lindestam Arlehamn, Anna Gerasimova, Ryan Henderson,Justine Swann, Jason A. Greenbaum, Yohan Kim, John Sidney, Denise M. McKinney, Howard Grey, Bjoern Peters and Alessandro Sette.
Models for the generation of heterogeneous MTB-responding T cells