Mycobacteria induce CD4⁺ T cells that are cytotoxic and display Th1‐like cytokine secretion profile: Heterogeneity in cytotoxic activity and cytokine secretion levels

Abstract

Protective immunity against mycobacteria is dependent on antigen-specific T cells. Current evidence suggests that not only helper T cells that activate infected macrophages but also cytotoxic T cells (CTL) that lyse infected macrophages are involved in protection. Mycobacterium-specific CD4+ CTL are readily detectable among primary peripheral T cells but what proportion of CD4+ T cells display cytotoxic activity is not known. Whether the cytotoxic CD4+ T cells are identical to or distinct from those that produce interferon (IFN)-gamma is also unknown. In addition, studies on CTL in mycobacterial infections have focused primarily on selected antigens like hsp65 but have not analyzed systematically whether other mycobacterial antigens can activate CTL as well. These issues are relevant not only to a further understanding of protective immunity and immunopathology but also may have implications for the design of effective vaccines. To start addressing these issues, we have studied a large panel of CD4+ T cell clones specific for a broad range of mycobacterial antigens, and analyzed their ability to lyse mycobacterium-pulsed target cells and to release IFN-gamma and interleukin (IL)-4. Our results show that the vast majority of CD4+ T cell clones are able to lyse mycobacterial antigen-pulsed target cells, and that those CTL can be triggered by a wide variety of mycobacterial antigens. CD4+ CTL released high levels of IFN-gamma, but low or nondetectable levels of IL-4. In contrast, control tetanus toxoid-specific T cell clones or lines displayed poor or weak cytotoxic activity and released high levels of IL-4. The antimycobacterial clones appeared to be heterogeneous in their levels of cytotoxic activity and IFN-gamma release. Interestingly one T cell clone was able to lyse only mycobacterium-pulsed macrophages but not B cells suggesting possible selectivity in target cell recognition for some CTL. These in vitro data have to be interpreted with some caution. Nevertheless they confirm and significantly extend previous observations and suggest that mycobacteria preferentially induce CD4+ T helper type 1 (Th1)-like cells that display cytotoxic activity, and release high levels of IFN-gamma but no or little IL-4. The induction of such Th1 like cells is specific for mycobacteria since tetanus toxoid induced T cells that were poorly or not cytolytic and secreted high levels of IL-4.

Rebuilding Human Leukocyte Antigen Class II–Restricted Minor Histocompatibility Antigen Specificity in Recall Antigen-Specific T Cells by Adoptive T Cell Receptor Transfer: Implications for Adoptive Immunotherapy

“…Therefore, a possible improvement of our methodology can be the direct selection of IFN-g -producing TT-specific T cells using clinically applicable immunomagnetic bead-based IFN-g capture assays (7). Selection of IFN-g -secreting cells may also have the advantage that TCRs will be preferentially targeted into CTLs because it is known that IFN-g secretion and cytotoxic activity of CD4 + cells are well correlated (27,28). In conclusion, we here present a feasible strategy to generate immunotherapeutic T cells directed against HLA class IIrestricted mHags.…”

Stimulation of suppressive T cell responses by human but not bacterial 60-kD heat-shock protein in synovial fluid of patients with rheumatoid arthritis.

“…Immunization of rats with whole heat-killed Mycobacterium tuberculosis , a T1 cell-promoting condition in humans and rodents (13,15), can lead to (adjuvant) arthritis in rats, which can be transferred by a T cell clone recognizing a 60-kD mycobacterial hsp (16). However, preimmunization with the isolated mycobacterial hsp60 can protect against the induction of adjuvant arthritis as well as other forms of experimental arthritis (17)(18)(19)(20)(21).…”

Mycobacterium tuberculosisSubverts Innate Immunity to Evade Specific Effectors

“…ϩ T cell responses, including responses with cytolytic activity against M. tuberculosis Ags, are found both in humans, especially in clinical settings characterized by an effective immunity such as tuberculous pleurisy (22)(23)(24)(25)(26)(27)(28) and in mice (29,30). Thus, induction of macrophage apoptosis by M. tuberculosis-specific CD4 ϩ T cells may operate in vivo to control M. tuberculosis survival.…”