It is well documented that IFN-γ plays an important role in the development of cellular immunity to Mtb. Humans with mutated IFN-γ receptor genes are highly susceptible to infection by atypical mycobacteria (43
). Consistent with these findings, mice with a disrupted IFN-γ gene fail to produce reactive nitrogen intermediates and restrict the growth of the bacilli although they develop granulomas (28
). This extreme model, in which the host is unable to produce any IFN-γ necessary for the generation of antimicrobial activity, demonstrates the requirement of IFN-γ for containment of mycobacterial infection. It is thus interesting to speculate that in anergic TB patients that have defective IFN-γ production in response to Mtb stimulation mycobacteria are not eradicated but survive in a persistent state in closed or encapsulated lesions, despite the absence of sputum AFB positivity.
Generation of IL-10–producing Tr1-type cells is a lengthy process that requires chronic antigen-specific stimulation of naïve T cells in the presence of IL-10 (17
). This notion is compatible with the long natural history of TB and the development of TB anergy. 0ur present findings suggest that in anergic patients, sustained stimulation by Mtb, which results in IL-10 but not IFN-γ production, mediates the generation of anergic Mtb-specific T cells with Tr1 phenotype and antigen-nonspecific immunosuppressive properties. Subsequently, in the presence of IL-10, the Mtb-infected host becomes tolerant to the Mtb antigens, similar to IL-10–treated animals that become tolerant to allogeneic antigens of the transplanted grafts (36
). Whether other cell subsets besides CD4+
T cells contribute to IL-10 secretion after Mtb-mediated stimulation and whether, in addition to IL-10, other immunoregulatory mechanisms suppress the immune response in the anergic TB patients, remains to be determined.
The development of Mtb-specific T-cell anergy due to chronic Mtb-mediated stimulation in the absence of IFN-γ and the presence of IL-10 may contribute to the establishment of Mtb persistence. Importantly, it has been suggested that although its mechanisms remain unknown, “persistence” may hold the key to the problems of defective eradication of Mtb, resistance to treatment, and relapse, through mechanisms independent of drug resistance (46
). Remarkably, increased IL-10 levels appear to promote Mtb survival and correlate with a more severe clinical phenotype of the disease, since IL-10–transgenic mice are highly susceptible to progressive TB infection and IL-10–deficient mice have increased antimycobacterial immunity (47
). It was shown recently that polymorphic variations of Plasmodium falciparum
can downregulate T-cell proliferative response by preferential induction of IL-10, potentially contributing to the low levels of responses to this pathogen in endemic areas (49
). Therefore, such downregulatory mechanisms of the host immune response, directly mediated by various infectious organisms, may prevent elimination of the pathogens and contribute to the low levels of antibacterial responses, reinfection due to the lack of immunity, and reactivation and relapse of the disease.
Recent in vitro studies have started to decipher the molecular pathways that are required for the induction of anergy. In addition, reports from murine and subhuman primates in in vivo models of allogeneic solid organ and bone marrow transplantation provide evidence that induction of alloantigen-specific anergy results in long-term graft acceptance (50
) and loss of graft versus host disease (52
). Moreover, ex vivo anergization enabled successful histoincompatible bone marrow transplantation in humans (54
). Our present studies extend those observations since they show the in vivo generation of anergy-specific biochemical events in the intact human host, and they provide evidence for the biologic significance of these findings in the pathophysiology of an infectious disease.
Finally, our results provide new insights into mechanisms by which Mtb escapes immune surveillance. The presence of immunosuppressive, IL-10–producing T cells and the detection of anergy-specific biochemical findings in the peripheral blood of anergic TB patients suggest that Mtb mediates active inhibition of the host immune response, resulting in sustained survival of the infectious organisms. Therefore, besides chemotherapy, methods to reverse the Mtb-induced anergy should be an integral part of novel treatment strategies attempting the cure and eradication of TB.