Influence ofMycobacterium bovisBacillus Calmette Guérin on In Vitro Induction of CD1 Molecules in Human Adherent Mononuclear Cells

Abstract

Nonpeptide antigens (including glycolipids of microbial origin) can be presented to T cells by CD1 molecules expressed on monocyte-derived dendritic cells. These HLA unrestricted responses appear to play a role in host immunity against Mycobacterium tuberculosis and other pathogenic bacteria. It is known that vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) has limited efficacy in many clinical settings, although the reasons for its inadequacy remain unclear. Here we have investigated the influence of BCG on the induction of CD1b on human monocytes by granulocyte-macrophage colony-stimulating factor (GM-CSF), which is believed to be the principal inducer of this antigen-presenting molecule. Although BCG alone led to a slight induction of CD1b expression, this agent reduced markedly the ability of GM-CSF to induce high levels of CD1b that were typically observed in uninfected cells. Inhibition of CD1b expression in BCG-infected monocytes was apparent at both the mRNA transcript and CD1b protein levels. Down-regulation of CD1b expression by BCG was mediated, at least in part, by one or more soluble factors and could not be reversed with high concentrations of GM-CSF or a variety of other cytokines. The present results suggest that BCG could diminish the efficiency of CD1-restricted T-cell responses against nonpeptide mycobacterial antigens by reducing CD1 expression on antigen-presenting cells. These findings have potential implications for understanding the nature of the immune response elicited by BCG in humans and suggest potential strategies that could be important for the development of better vaccines for the prevention of tuberculosis.Data from the world literature show that morbidity and mortality from mycobacterial infections are continuously increasing (3,9,17). This appears to be due not only to a higher transmission rate of the disease, especially in immunocompromised human immunodeficiency virus (HIV)-infected patients (2, 5), but also to the emergence of multidrug-resistant strains of Mycobacterium tuberculosis (17,21,25). Therefore, effective early vaccination of individuals at high risk for developing active tuberculosis has been targeted as an important approach for tuberculosis control. Vaccination against M. tuberculosis has been attempted on a large scale using Mycobacterium bovis bacillus Calmette-Guérin (BCG), a live attenuated strain. However, the results of clinical trials that enrolled an extraordinary number of cases immunized with BCG were not consistently appealing (24,29). A recent meta-analysis of the literature showed that the vaccine significantly reduces the risk of tuberculosis by an average of only 50% (4). The reasons why BCG does not provide optimal protection are not clear, since the organism is known to share a number of major histocompatibility complex (MHC)-restricted antigens with virulent M. tuberculosis and also activates ␥␦ T cells that may facilitate the responses of CD4 ϩ and CD8 ϩ responder T cells that are important in maintaining immunity to M. t...

Activating Transcription Factor/cAMP Response Element Binding Protein Family Member Regulated Transcription of CD1A

“…Interestingly, it has been reported that forskolin treatment of GM-CSF/IL-4-derived dendritic cells have decreased CD1a expression, consistent with our cell line data (32). Similarly to CD1A, ATF/CREB family members can be altered in multiple sclerosis, various cancers, and M. tuberculosis-infected cells (14,15,(43)(44)(45)(46). Thus, examining alteration of ATF/CREB family members could lead to insight into CD1a expression, as well as function and activation of CD1a-restricted T cells.…”

“…CD1a expression is also altered in various human infections. Both bacillus Calmette-Guérin and Mycobacterium tuberculosis infection result in demonstrable change in CD1a, b, and c surface expression (15,16). In addition, a strong correlation between CD1 expression and effective host immunity in leprosy has been reported (17).…”

Host-derived oxidized phospholipids and HDL regulate innate immunity in human leprosy

“…Purified PEIPC, but not POVPC, recapitulated the inhibitory effects of oxPAPC on CD1 expression (Supplemental Figure 1D). Therefore, as with mycobacterial infection (31,32), PEIPC inhibited expression of CD1 molecules on differentiating DCs. In contrast, fractions enriched in PEIPC did not inhibit expression of MHC class II on monocyte-derived DCs ( Figure 4B).…”

“…A key cell of the innate immune system is the DC, whose differentiation can be followed by the expression of CD1 molecules, which are themselves antigen-presenting elements for lipid antigens to T cells. Previously, independent groups have shown that oxLDL (30) and mycobacterial infection (31,32) cause suppression of CD1 molecules on DCs. Furthermore, oxPAPC has been demonstrated to prevent the maturation of immature DCs (29).…”

CD1-Restricted T Cells in Host Defense to Infectious Diseases

“…These findings were interpreted as possible evidence of an immune evasion mechanism used by M. tuberculosis to avoid recognition through presentation of its antigens by CD1. Subsequent studies examining the effects of M. bovis BCG on the ability of CD1b to be induced on monocytes by exposure to GM-CSF also found evidence for inhibition of CD1 expression by live mycobacterial infection [11,12]. A similar downmodulation of group 1 CD1 expression and blockade of CD1 induction by GM-CSF has been shown to occur with infection of human monocyte-derived dendritic cells in vitro with the intracellular protozoan Leishmania donovani [13].…”