Title:
Functional Signatures of Human CD4 and CD8 T Cell Responses to Mycobacterium tuberculosis.

Abstract:
With 1.4 million deaths and 8.7 million new cases in 2011, tuberculosis (TB) remains a global health care problem and together with HIV and Malaria represents one of the three infectious diseases world-wide. Control of the global TB epidemic has been impaired by the lack of an effective vaccine, by the emergence of drug-resistant forms of Mycobacterium tuberculosis (Mtb) and by the lack of sensitive and rapid diagnostics. It is estimated, by epidemiological reports, that one third of the world's population is latently infected with Mtb, but the majority of infected individuals develop long-lived protective immunity, which controls and contains Mtb in a T cell-dependent manner. Development of TB disease results from interactions among the environment, the host, and the pathogen, and known risk factors include HIV co-infection, immunodeficiency, diabetes mellitus, overcrowding, malnutrition, and general poverty; therefore, an effective T cell response determines whether the infection resolves or develops into clinically evident disease. Consequently, there is great interest in determining which T cells subsets mediate anti-mycobacterial immunity, delineating their effector functions. On the other hand, many aspects remain unsolved in understanding why some individuals are protected from Mtb infection while others go on to develop disease. Several studies have demonstrated that CD4(+) T cells are involved in protection against Mtb, as supported by the evidence that CD4(+) T cell depletion is responsible for Mtb reactivation in HIV-infected individuals. There are many subsets of CD4(+) T cells, such as T-helper 1 (Th1), Th2, Th17, and regulatory T cells (Tregs), and all these subsets co-operate or interfere with each other to control infection; the dominant subset may differ between active and latent Mtb infection cases. Mtb-specific-CD4(+) Th1 cell response is considered to have a protective role for the ability to produce cytokines such as IFN-γ or TNF-α that contribute to the recruitment and activation of innate immune cells, like monocytes and granulocytes. Thus, while other antigen (Ag)-specific T cells such as CD8(+) T cells, natural killer (NK) cells, γδ T cells, and CD1-restricted T cells can also produce IFN-γ during Mtb infection, they cannot compensate for the lack of CD4(+) T cells. The detection of Ag-specific cytokine production by intracellular cytokine staining (ICS) and the use of flow cytometry techniques are a common routine that supports the studies aimed at focusing the role of the immune system in infectious diseases. Flow cytometry permits to evaluate simultaneously the presence of different cytokines that can delineate different subsets of cells as having "multifunctional/polyfunctional" profile. It has been proposed that polyfunctional T cells, are associated with protective immunity toward Mtb, in particular it has been highlighted that the number of Mtb-specific T cells producing a combination of IFN-γ, IL-2, and/or TNF-α may be correlated with the mycobacterial load, while other studies have associated the presence of this particular functional profile as marker of TB disease activity. Although the role of CD8 T cells in TB is less clear than CD4 T cells, they are generally considered to contribute to optimal immunity and protection. CD8 T cells possess a number of anti-microbial effector mechanisms that are less prominent or absent in CD4 Th1 and Th17 T cells. The interest in studying CD8 T cells that are either MHC-class Ia or MHC-class Ib-restricted, has gained more attention. These studies include the role of HLA-E-restricted cells, lung mucosal-associated invariant T-cells (MAIT), and CD1-restricted cells. Nevertheless, the knowledge about the role of CD8(+) T cells in Mtb infection is relatively new and recent studies have delineated that CD8 T cells, which display a functional profile termed "multifunctional," can be a better marker of protection in TB than CD4(+) T cells. Their effector mechanisms could contribute to control Mtb infection, as upon activation, CD8 T cells release cytokines or cytotoxic molecules, which cause apoptosis of target cells. Taken together, the balance of the immune response in the control of infection and possibly bacterial eradication is important in understanding whether the host immune response will be appropriate in contrasting the infection or not, and, consequently, the inability of the immune response, will determine the dissemination and the transmission of bacilli to new subjects. In conclusion, the recent highlights on the role of different functional signatures of T cell subsets in the immune response toward Mtb infection will be discerned in this review, in order to summarize what is known about the immune response in human TB. In particular, we will discuss the role of CD4 and CD8 T cells in contrasting the advance of the intracellular pathogen in already infected people or the progression to active disease in subjects with latent infection. All the information will be aimed at increasing the knowledge of this complex disease in order to improve diagnosis, prognosis, drug treatment, and vaccination.