The role of CD8+ T cells in immunity to tuberculosis infection

I t has become increasingly clear over the past decade that the T cell response to Mycobacterium tuberculosis infection in experimental mouse models is a complex event involving different functional populations of cells drawn from all three of the major T cell groups, namely CD4 ÷, CD8 ÷ and 75 cells. Much of the emphasis of recent research has concentrated on the CD4 response, given the capacity of such cells in adoptive transfer experiments to provide both protective immunity and memory immunity 1,2, and in view of the large amounts of gamma-interferon (IFN-7) that these cells secrete when cultured in vitro with mycobacterial antigens 3-s. Nevertheless, there is limited evidence that CD8 + T cells are also involved. For instance, CD8 ÷ cells have been shown to be weakly protective in transfer assays 1, perhaps as a result of their capacity to secrete low levels of IFN-7 (Ref. 5), and cytolytic CD8 ÷ T cell lines have been generated from mice inoculated with dead bacilli 6. However, the possible importance of the CD8 ÷ T cell response, both from the perspective of acquired immunity to tuberculosis and from the perspective of vaccine development, has not yet been clearly defined. Of considerable interest, therefore, is a recent report 7 by Flynn and her colleagues at the Albert Einstein College of Medicine, which shows that mice in which the J]2-microglobulin gene has been disrupted (the practical consequence of which is an inability to express class I MHC molecules and hence a complete lack of functional CD8 ÷ T cells) are highly susceptible to infection with a normally sublethal dose of M. tuberculosis. In such animals, the infection is not adequately contained, and gives rise to extensive lung pathology including evidence of caseous necrosis, resulting in the death of these mice four to ten weeks after inoculation. This report is particularly timely, on two counts. First, it serves to resurrect interest in the possible role of CD8 + cells in protective immunity to mycobacteria; and second, it heralds one of the first uses in infectious disease research of the new generation of animal models based on targeted gene disruption. These targets include, in addition to J32-microglobulin, the o~J5 T cell receptor and cytokines such as IFN-7 (Ref. 8). However, these models must still be used with caution, especially when a major element like [32microglobulin is disrupted that may also have other physiological consequences. For instance, in the model described by Flynn and her colleagues, 75% mortality of infected mice was observed by four weeks, despite very similar bacterial levels in the lungs of test and control mice (in my experience, the lung counts are a good predictor of potential mortality). In addition, T cells from such mice failed to produce IFN7 in vitro to bacterial protein antigens, but did so to a bacterial sonicate. While this latter result is rather curious, it may indicate that a concerted effort by both CD4 + and CD8 ÷ cells, in terms of cytokine secretion, and perhaps cytolysis s'6'9, is needed to contain the virulent infection adequately. Both the results of the Flynn study and an older report from this laboratory 1 seem to suggest that CD8 ÷ cells may be especially important in the lungs. This obser-