Cell-mediated immune responses in tuberculosis

Abstract

Tuberculosis is primarily a disease of the lung, and dissemination of the disease depends on productive infection of this critical organ. Upon aerosol infection with Mycobacterium tuberculosis (Mtb), the acquired cellular immune response is slow to be induced and to be expressed within the lung. This slowness allows infection to become well established; thus, the acquired response is expressed in an inflammatory site that has been initiated and modulated by the bacterium. Mtb has a variety of surface molecules that interact with the innate response, and this interaction along with the autoregulation of the immune response by several mechanisms results in less-than-optimal control of bacterial growth. To improve current vaccine strategies, we must understand the factors that mediate induction, expression, and regulation of the immune response in the lung. We must also determine how to induce both known and novel immunoprotective responses without inducing immunopathologic consequences.

Figure 1

Low dose aerosol infection, which approximates the natural delivery route for induction of tuberculosis, results in low numbers of Mtb (green) being deposited in the lower airways and the alveolar tissue. Bacteria do not disseminate from the lung until 9 days post infection when they can be detected in the draining lymph nodes. This dissemination coincides with the first activation of naive T cells (pink). The fact that bacteria do not disseminate rapidly, suggests that they either inhibit migration of dendritic cells or that the cells that they infect cannot migrate readily to the lymph node. Activation of naive T cells occurs in the presence of live bacteria and effector cells develop with expected kinetics. The effector cell phenotype will depend upon the availability of specific cytokines. These effector cells migrate to the lung in response to inflammation and mediate protection by activating infected phagocytes (red). The response takes 18–20 days to reach an effective level and to thereby stop bacterial growth.

Figure 2

The inflammatory lesion within the lung is a dynamic environment containing a variety of protective and regulatory cells. Effector T lymphocytes (pink) mediate control of bacterial growth and the mononuclear composition of the granuloma. Regulatory T lymphocytes (red) also accumulate in the lesion and limit the ability of the acquired response to stop bacterial growth. Infected phagocytes elaborate cytokines and effector molecules that limit the activity of the lymphocyte response. B cells (blue) accumulate within the lesion in the form of nascent lymphoid follicles; these cells can impact bacterial control and the immunopathologic consequences of infection. Mtb (green) can modulate the inflammatory response via the modification of TDM expressed at the bacterial surface.

Figure 3

(A) The host with previous antigenic experience has an increased frequency of memory lymphocytes either in the circulation (pink) or within the lung (green). Cells within the lung can respond to infection before bacteria migrate to the lymph node and can therefore activate infected phagocytes and stop bacteria growth. Cells within the lung can also recognize infection and act to rapidly to recruit circulating memory cells that may require dissemination of bacteria to become activated. As effector cells arrive in the lung they activate phagocytes and stop bacterial growth. (B) The cessation of bacterial growth by memory cells can occur 5 days sooner than is seen for naive cells. This acceleration though significant does not stop substantial bacterial growth and thus effector cells must act within a site that has been initiated and modulated by Mtb. If the memory response can be improved such that the response occurs within 10 days as opposed to 15 then the T cell response may be expressed more efficiently and thereby limit the development of disease.