In accordance with this line of thought are findings from a recent study of hepatitis C virus showing that short-term cytokine responses were not influenced by depletion of CCR7+ T cells (most likely representing central memory cells), whereas the depletion

of CCR7+ T cells Bafilomycin A1 clinical trial decreased cytokine response after prolonged culture 29. From these results, we speculate that the functional signatures of CD4+ T-cell subsets during anti-mycobacterial response could be detected using different times of in vitro stimulation (short versus long term) irrespective of the use of mycobacterial peptides versus proteins, because of the presence of different subsets of CD4+ T cells that need more time to rescue from the resting state 30. According to the scheme proposed by Seder et al.31, CD4+ T-cell differentiation can be modelled as a linear process, in which cells progressively gain functionality with further differentiation, until they reach the stage that is optimized see more for their effector function. Continued antigenic stimulation can lead to the generation of central memory multifunctional cells (which produce simultaneously IFN-γ, IL-2 and TNF-α) and then to the progressive loss of memory potential as well as cytokine production (effector

memory 2+ cells producing IL-2 and IFN-γ), resulting in terminally differentiated CD4+ T cells that only produce IFN-γ and are short lived. According to Seder, the amount of initial antigen exposure will govern the extent of differentiation, with high-antigen

stimulation leading to completion of this proposed differentiation pathway. How do our results fit with this differentiation pathway? The finding that multifunctional 3+ cells are detected in patients with active disease, but not in LTBI subject or cured TB patients, almost suggests that the LTBI cases or patients with cured TB disease, have passed the stage of multifunctional 3+ T cells already and are now effector memory cells. This implies that it is rather the presence of 2+ effector memory cells which is associated with the lack of TB disease or successful control of M. tuberculosis infection by the immune system. Alternatively, or in addition (-)-p-Bromotetramisole Oxalate to, it has been proposed 28 that multifunctional CD4+ T cells represent a population of antigen-primed T cells which return to a resting state by default in the absence of antigen contact. This possibility should explain why we failed to detect multifunctional T cells in LTBI subjects and cured TB patients in the short-term stimulation assay which measure only the recently primed CD4+ T cells, but no T cells that returned to a resting state 27, 28. Finally, multifunctional activity of CD4+ T cells in TB patients may be suppressed by simultaneous presence of Treg cells or by monocytes/macrophages/DC products as TGF-β or IL-10.