Our data D-Pantothenic acid sodium clearly reveals that both PD-1 and ICOS either separately or together mark Tfh cells with similar properties in terms of antigenic responsiveness. Subsequently, the examination of frequencies of these Tfh subsets revealed a significant reduction in the frequencies of these subsets in those with PTB. This study demonstrates for the first time, we believe, that there are decreased frequencies of Tfh cells in tuberculosis, data that are in contrast to data from HIV and other viral infections where Tfh frequencies are increased. Thus, PTB appears to be selectively associated with TB – antigen specific deficiency in Tfh cells expressing either ICOS and/or PD-1. One of the major hallmarks of Tfh cells is their ability to produce a variety of cytokines – most notably IL-21. Our examination of the IL-21 expressing Tfh cells in PTB reveals that the diminished frequency of Tfh cells in TB disease translated to diminished function of these cells. In addition, we also observed significantly diminished systemic levels of IL-21 in PTB and a significant positive correlation between Tfh cell subset frequencies and IL-21 levels in these Tulathromycin B individuals suggesting that most of the IL-21 in TB infection and disease is probably derived from circulating Tfh cells. Since there are increasing reports of Tfh cells producing other cytokines including IL-4, IFNc and IL-17, we examined the levels of these cytokines and found lower levels of circulating IFNc in PTB. Thus, we demonstrate that the dysregulated expression of Tfh 
cell subsets is actually associated with functional impairment of these cells in the circulation of PTB individuals. It is possible that the diminished frequencies in the blood of PTB individuals is a reflection of increased migration to the tissues – lungs or mediastinal lymph nodes. However, since circulating Tfh cells have been shown to consistently exhibit additional functions compared to tissue resident Tfh cells, our data hold importance in terms of potential impact on pathogenesis of TB disease. However, we have not examined the frequencies of these cells or that of their hallmark cytokines in healthy control individuals and therefore need to perform these studies in the future to elucidate the role of these cells and cytokines in TB infection. Another hallmark of Tfh cells is their ability to provide B cell help. Although the role of B cells in TB is not clearly understood, it is known that B cell deficient mice appear more susceptible to TB. Studies of human and non human primate TB granulomas have identified B cell follicle structures that might contribute to the immune response to TB. While conventional Tfh cells are known to promote all aspects of B cell function, circulating Tfh cells are known only to specifically promote activated and classical memory B cell and plasma cell formation. However, we did not observe any significant compromise in memory B cell formation in PTB nor were there any perturbations in frequencies of other B cell subsets. Again, we have not estimated the function of these cells directly nor have we estimated the frequency of these cells in healthy control indviduals. Although it is known that numerous cytokines can promote Tfh formation, much less is known about the factors that restrain this process. It has been reported that Tfh cell formation can be suppressed by several cytokines, including IL-10 and TGFb. Indeed, we also detected increased levels of IL-10 in circulation in PTB individuals. Coupled with data on the blockade of IL-10 in PTB individuals, it appears that IL-10 does indeed play an important role in the modulation of Tfh cells in active PTB. On the other hand, TGFb appears to play a negligible role in the regulation of Tfh cells in active TB.