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Divisions of
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Pulmonary and Critical Care Medicine and Infectious Diseases, Case Western Reserve University School of Medicine, and
University Hospitals of Cleveland, Cleveland, OH 44106
Protective human immunity to Mycobacterium tuberculosis(M. tb) has proven difficult to
characterize, in part because of technical obstacles to in vitro
infection of human cells with virulent M. tb. We
established a reproducible method of infecting human monocytes (MN)
with the virulent M. tb strain H37Rv that did not reduce MN
viability. TNF-
had no effect on replication of H37Rv within MN, and
IFN-
mediated only a 1.9-fold reduction in bacterial growth. In
contrast, nonadherent cells (NAC) from purified protein derivative
(PPD)-positive and PPD-negative subjects reduced intracellular growth
of H37Rv by 6- and 10.6-fold, respectively (p
= 0.007 and p = 0.005). CD4+ T cells were
essential to growth inhibition mediated by NAC of PPD-positive
subjects, whereas containment of M. tb by NAC of
PPD-negative subjects did not require CD4+ cells.
CD8+ T cells did not contribute to protection mediated by
NAC of either group. Supernatants of cocultured H37Rv-infected MN and
NAC only partially reduced intracellular growth of M. tb
despite containing nanogram concentrations of TNF- and IFN-.
Neutralizing antibodies to TNF-, IFN-, and IL-12 failed to affect
the NAC-mediated growth limitation. NAC treated with emetine retained
approximately 40% of their capacity to contain intracellular H37Rv,
however. These studies indicate that protective human recall responses
to M. tb are mediated primarily by CD4+ T
cells, whereas CD4-CD8- lymphocytes may
contribute to innate immunity to M. tb. The ability of NAC
to activate M. tb-infected MN is only partly attributable
to soluble mediators and may also involve contact-mediated mechanisms.
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