It has, for many years, been widely assumed that the fundamental mechanism of protection in
tuberculosis infection is a CD4 T cell response producing
lymphokines that activate macrophages to kill or restrict the intracellular growth of M.
tuberculosis. Just as certain
cytokines, e.g. IFN-gamma, are currently perceived to be important for protection, others, particularly
tumor necrosis factor (TNF), are thought to be responsible for much of the tissue destruction associated with the disease. Yet there are remarkably few critical experimental or clinical data that have defined the immunological requirements for protection and pathogenesis. One of the initial stimuli to the work we have undertaken has been careful reflection on the results of the many prospective trials of BCG against
tuberculosis. Two aspects have impelled us to reconsider conventional wisdom. The first, of course, is the wide discrepancy in the degree of protection imparted, ranging from 0% in South India to 77% in the British MRC trial (1, 2). The second is that, in all trials that examined them, skin test conversions to
tuberculin positivity were 85% or greater, indicating a disparity between the presence of
delayed hypersensitivity to
tuberculin and protection. We and others have argued (1, 2) that there are multiple possible explanations for this discrepancy, the principal one being protection caused by
infection with environmental mycobacteria. But, the general point raised is whether cell mediated immunity as manifested by CD4+ cell production of
lymphokines and macrophage activation is a sufficient mechanism for protection against M.
tuberculosis infection.