**3. T cell activation against** *Mycobacterium tuberculosis*

In human, a TB index case may infect a contact person through cough and expectoration, so the lung is the primary route of infection and often the main tissue exhibiting TB. Infec‐ tious droplet nuclei are deposited in the alveolar spaces of the contact person where *Myco‐ bacterium tuberculosis (M. tb)* can be phagocytosed by alveolar macrophages, epithelial cells, dendritic cells (DC) and neutrophils [8, 9]. Alveolar macrophages and DC are then believed to transport *M. tb* to local lymph nodes where T cell activation occurs and expand. Activa‐ tion of the phagocytic host cell is much required to limit growth of *M. tb*; as in the absence of activation, disease outcome is extremely poor. Effective phagocyte activation requires a specific cellular response, as infected hosts lacking specific components of the acquired re‐ sponse have a poor outcome [10]. While acquired cellular protection is expressed rapidly following systemic challenge with *M. tb*, it is less rapid in the lung. Slow expression of pro‐ tection in the lung allows mycobacteria to grow and modulate the infection site. Until re‐ cently it has not been clear whether the slow response to aerosol delivery of bacteria resulted from limited availability of antigen or inhibition of antigen-presentation by *M. tb*. Several studies show that the first T cell activation occurs in the draining lymph node (DLN) of the lung 8–10 days following initial challenge. The activation of T cells correlated temporally with the arrival of bacteria and availability of antigen in the DLN, however con‐ ditions for T cell activation were unique to the draining lymph nodes as the presence of an‐ tigen-producing bacteria in the lung and spleen did not result in initial activation of T cells [11, 12]. While delivery of lipopolysaccharide (LPS) to the MTB-infected lung failed to ac‐ celerate T cell priming [11], increasing the bacterial dose did accelerate the response mod‐ estly suggesting that both antigen burden and refractory cells serve to slow the response. So, protective memory cells will not become activated until they see antigen, i.e. more than 8 days post infection. Once T cells become activated they differentiate into effector T cells that migrate to the lung. By day 14 of infection, when activated T cells first arrive in the lung, bacteria are within alveolar macrophages, myeloid DC and neutrophils [11]. T cells can recognize antigen within the mycobacterially-infected lung but the antigen presenta‐ tion is not optimal. It takes time for the protective T cells to reach sufficient numbers to stop bacterial growth. T cells can be divided into two subsets, Th1 and Th2, on the basis of the cytokines they produce. In tuberculosis, Th1 plays a major role in defense against tuber‐ culosis. Th1 cells suppress Th2 cells. CD4 + T cells have unambiguously been identified as the most important lymphocyte subset for mediating protection.CD4 T lymphocytes differ‐ entiate in the peripheral tissues to adopt a variety of fates such as the Th-1 cells, which pro‐ duce interferon (IFN)-*γ* to down-regulate Th2 responses and Th-2 cells, which produce interleukin (IL)-4. CD8 T lymphocytes produce predominantly IFN-*γ*. Though CD4 re‐ sponse is greater than the CD8 response, the latter can provide protection in the absence of CD4 help [13]. During active TB there is a local pulmonary immune response characterized by α/β T cells and strongly enhanced *M. tuberculosis* antigen-specific Th1 responses, with large amounts of locally secreted IFN-*γ* [14].

however, pulmonary lesions in guinea pig contain a high proportion of granulocytes, partic‐ ularly eosmophils, which are not common features of human disease [20]. The rabbit is the only common laboratory animal in which the disease closely resembles the typical chronic cavitary type found in the majority of human beings [21, 22]. Rabbits infected with *M. tb* mount a moderate DTH response and form caseous granulomas and cavitary lesions [23-25]. Rabbits, including currently available inbred strains, are relatively resistant to *M. tb*, however, requiring the inhalation of 500 to 3000 bacilli to form one grossly visible tubercle at 5 weeks postinfection [23]. Most rabbits will also overcome disease completely, with few culturable bacilli [24]. This model is useful in the study of latent or paucibacillary TB states, however, without the use of antibiotics as in the Cornell model. Rabbits do need to be experimentally immunosuppressed as they will not spontaneously reativate disease [26]. There are minimal immune reagents, however, for this model, and the larger size of rabbits makes them more costly to use. There are inbred strains of rabbits, such as the Lurie and Thorbecke rabbits, which are more suscep‐ tible to *M. tb* infection. This susceptibility has been linked to suppressed macrophage antimy‐ cobacterial activity, decreased MHC Class 2 expression, and impaired development of type 4 hypersensitivity [27]. Other animal models, such as nonhuman primates, which are susceptible to *M. tb* and full spectrum of granuloma types can be observed [28], have not been widely used. Using mycobacterial inoculation into trachea, at necropsy, all unvaccinated monkeys (*Macaca fascicularis* and *Macaca mulatta*) exhibited extensive bilateral lung pathology characterized by the presence of multiple granulomas. These granulomas exhibited conglomeration to larger

Pathophysiology of Tuberculosis http://dx.doi.org/10.5772/54961 131

When tubercle bacilli reach alveoli, they are phagocytosed by resident alveolar macrophages. Though tubercle bacilli are killed byalveolar macrophages, tubercle bacilli can also kill macrophages through apoptosis. What is the fate of tubercle bacilli once they enter the phagosomes of macrophages? Alveolar macrophages of aerially infected guinea pigs were collected by bronchoalveolar lavage. At 12 days after infection, one out of 10,000 alveolar macrophages of various sizes contained many tubercle bacilli [31]. This indicates that certain alveolar macrophages permit M. tuberculosis to replicate in the phagosomes, although most of tubercle bacilli are killed by activated alveolar macrophages. It will be of great interest to examine the survival mechanism of *M. tuberculosis* at the single-cell level, but we still do not

IFN-γ knockout mice were infected with avirulent H37Ra or BCG Pasteur, multinucleated giant cells were recognized in the granulomatous lesions. The lesions also contained tubercle bacilli and consisted of multinucleated cell clusters, being immunopositive with anti-Mac-3 antibody. The alveolar macrophages were transformed into multinucleated ginat cells. We subsequently infected various cytokine-konockout mice with *M. tb*, but no Langerhans' multinucleated giant cells were recognized in the granulomas. Therefore, it seems that formation of multinucleated giant cells requires optimal combinations and concentrations of

know why macrophages targeted by tubercle bacilli cannot kill the bacilli.

various cytokines, and the level of IFN-γ, at least, has to be significantly low.

caseous areas, especially in the hilar region [55].

**5. Alveolar macrophages in tuberculosis**
