IL-10–producing T cells suppress immune responses in anergic tuberculosis patients

Abstract

IntroductionClinical conditions that induce impaired cell-mediated immunity like AIDS, malignancy, and immunosuppressive therapy result in impaired MHC class II-mediated delayed-type hypersensitivity (DTH) reaction (1, 2). Moreover, long-standing clinical observations have established that certain diseases that do not induce a generalized immunosuppressive state, also induce impaired DTH reaction to specific antigens, a state clinically defined as "anergy." Classical paradigms of these diseases include tuberculosis (TB), sarcoidosis, and Hodgkin's disease.TB is the leading cause of death from infectious diseases worldwide (3), accounting for eight million new cases and three million deaths annually (6). The lethality of TB is due to both the absence of an effective vaccine and to the poor understanding of how the mycobacteria escape immune surveillance. Anergy in the setting of TB refers to the paradoxical absence of dermal reactivity to intradermal injection with tuberculin purified protein derivative (PPD) in infected persons. It occurs in about 15% of patients with active pulmonary disease and is associated with absence of granuloma formation and all other manifestations of cellular hypersensitivity (3-5). We thus chose to examine the biochemical events that regulate the induction of TB anergy since this understanding may also provide insights into the pathophysiology of this disease.Anergy in vitro and its in vivo counterpart, tolerance, are immunologically defined as the inability of antigenspecific T cells to produce IL-2 and clonally expand on rechallenge with fully competent antigen-presenting cells (APC) (7,8). Induction of anergy is an active signaling process induced when T-cell receptor (TCR) is ligated by antigen without costimulation. Anergy can also be induced in the presence of costimulation if the TCR is ligated by superantigen or by altered peptide ligands that bear a single amino acid substitution in the sequence of the agonistic peptide (9). Although quite distinct, these three approaches to induce anergy appear to share common biochemical events characterized by hypophosphorylation of TCRζ and defective activation of ZAP-70 and Ras (10-15), indicating the generalized significance of these findings in the anergic state. Recently, IL-10 in The lethality of Mycobacterium tuberculosis remains the highest among infectious organisms and is linked to inadequate immune response of the host. Containment and cure of tuberculosis requires an effective cell-mediated immune response, and the absence, during active tuberculosis infection, of delayedtype hypersensitivity (DTH) responses to mycobacterial antigens, defined as anergy, is associated with poor clinical outcome. To investigate the biochemical events associated with this anergy, we screened 206 patients with pulmonary tuberculosis and identified anergic patients by their lack of dermal reactivity to tuberculin purified protein derivative (PPD). In vitro stimulation of T cells with PPD induced production of IL-10, IFN-γ, and proliferation in PPD +...

ICOS cooperates with CD28, IL‐2, and IFN‐γ and modulates activation of human naïve CD4+ T cells

“…It is noteworthy that secretion of both IL-10 and IFN-c is typical of Tr1 [43]. Moreover, ICOS induced expression of TGF-b1 and FoxP3, typical of naturally occurring CD4 + CD25 + Treg, together with expression of IL-10 [21,[37][38][39][40][41][42]. Intriguingly, expression of TGF-b1 and FoxP3 was induced at substantial levels, even by stimulation of CD3+ICOS in the absence of the support given by CD28 triggering or exogenous IL-2, when minimal levels of most cytokines were induced.…”

“…A different point is the effect of ICOS on induction of naïve CD4 + T cells toward Treg, which is relevant to the question whether Treg are generated from naïve T cells or Th1 and Th2 cells that have undergone chronic stimulation [21,[37][38][39][40][41][42]. This possibility is suggested by the finding that ICOS costimulates secretion of IL-10, particularly in the presence of high levels of IL-2 and in the absence of IFN-c.…”

Identification of a human CD8+regulatory T cell subset that mediates suppression through the chemokine CC chemokine ligand 4

“…Tregs have been isolated from leprosy patients (12,13), which suppressed CD4 ϩ Th1 cells (12)(13)(14). More recently, IL-10-producing T cells were reported in anergic TB patients (15), and increased frequencies of CD4 ϩ CD25 HI T cells have been found in the circulation of TB patients (16,17). Thus, mycobacterial infections may provide a highly relevant model to dissect immuneregulatory pathways in humans.…”

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

“…Despite the mechanisms of immune evasion that M. tuberculosis has evolved, a robust immune response may be measured in both active disease and LTBI, with the exception of advanced stages of active diseases that are characterized by anergic T cell responses (8). However, the host immune response may represent a double-edged sword in different TB stages: it has certainly a protective role, but it may also be detrimental to the host and instrumental to M. tuberculosis to infect other individuals (9).…”