Macrophage – T cell interaction in experimental mycobacterial infection. Selective regulation of co‐stimulatory molecules on Mycobacterium‐ infected macrophages and its implication in the suppression of cell‐mediated immune response

The most important immunopathological consequence of experimental mycobacterial infection is the suppression of T cell‐mediated immune response to both mitogens and mycobacterial antigens. We registered that there was decreased concanavalin A‐induced spleen cell proliferation in infected susceptible BALB/c mice as compared to normal mice. In resistant (C3H/HeJ) mice, infection with the bacteria did not induce any suppression in the mitogen‐induced lymphoproliferation. Likewise, delayed‐type hypersensitivity (DTH) responses, to keyhole limpet hemocyanin and mycobacterial crude soluble antigen were suppressed in infected BALB/c mice but not in C3H/HeJ mice. This depressed T helper cell function may either be due to defective T cell‐receptor occupancy by antigen‐Ia complex or altered co‐stimulatory signals provided by antigen‐presenting cells. In the present study, we have investigated the status of certain co‐stimulatory molecules on the infected macrophages from both susceptible and resistant mice. Our results demonstrate that upon mycobacterial infection, the macrophages are rendered incapable of delivering the co‐stimulatory signals to T helper cells, possibly due to the involvement of prostaglandin, as inhibition of its biosynthesis by indomethacin reversed the defect. Furthermore, the selective regulation was bacteria‐induced as killing of the bacteria by rifampicin abrogated the derangements in the expression of co‐stimulatory molecules on the Mycobacterium‐infected macrophages. Our observations revealed that upon infection with Mycobacterium tuberculosis, B7 was down‐regulated while ICAM‐1 was increased only in BALB/c but not in C3H/HeJ mice. Expression of VCAM‐1 did not change during the infection in either strain of mice. We found that these changes in ICAM‐1 and B7 expression on the surface of infected macrophages resulted in inhibition of DTH‐mediating functions of T helper cells from BALB/c mice. The results obtained in this study describe not only a novel immune evasion strategy adopted by Mycobacterium, but also open up the possibility of immunotherapy of mycobacterial infection by selective manipulation of co‐stimulatory molecules.