CD8 T Cells in Old Mice Contribute to the Innate Immune Response to Mycobacterium tuberculosis via Interleukin-12p70-Dependent and Antigen-Independent Production of Gamma Interferon

Elderly individuals have increased morbidity and mortality associated with infectious diseases due in part to the progressive age-associated decline in immune function. Despite this, the old mouse model of Mycobacterium tuberculosis infection has revealed a CD8- and gamma interferon (IFN-γ)-dependent early resistance to infection. In this study, we investigated the mechanism by which CD8 T cells from old mice contributed to the early immune response to M. tuberculosis. Following a low-dose aerosol infection with M. tuberculosis, CD8 T cells were identified as being a dominant source of IFN-γ expression in the lungs of old mice early after infection, before the typical onset of antigen-specific immunity. In addition, M. tuberculosis-induced IFN-γ production by CD8 T cells isolated from naïve old mice was major histocompatibility complex class I independent but was dependent on interleukin-12p70, confirming an innate role of CD8 T cells during M. tuberculosis infection. Moreover, the ability of CD8 T cells from old mice to produce increased innate IFN-γ levels in response to M. tuberculosis infection was defined as a unique function of CD8 T cells from old mice and not the aged lung environment. Finally, we have identified increased expression of SET as being one possible mechanism by which CD8 T cells from old mice produce enhanced levels of IFN-γ. Additional characterizations of the signaling events that lead to enhanced innate IFN-γ production by CD8 T cells in old mice may lead to novel strategies to further enhance or perpetuate beneficial immune responses in the elderly.The world''s elderly population is rapidly expanding and is predicted to reach 1.5 billion by the year 2050, a 28% increase since 2000 (http://esa.un.org/unpp/). The largest concentration of elderly individuals (projected to be 78% by the year 2050) is in developing countries (http://esa.un.org/unpp/), where many infectious diseases, including tuberculosis (35), are endemic. Given the increased susceptibility of the elderly to infectious diseases, this rapid rise in the elderly population poses a significant threat to global health care. Research focused on characterizing the immune response of the elderly to pathogens that cause substantial morbidity and mortality in elderly individuals is an area that has been significantly neglected; however, such studies would have a considerable impact on the prevention and treatment of infectious diseases in the elderly.As an individual ages, significant immunological changes occur, which contribute to the enhanced morbidity and mortality associated with infectious diseases in the elderly. After puberty, thymic atrophy leads to a progressive decrease in the output of naïve T cells and decreased diversity in the T-cell repertoire (7). Consequently, the periphery of an elderly individual is dominated by antigen-experienced or memory T cells, leading to a significant impairment of immune responses to new antigenic challenges (36). In addition to the immune defects in the T-cell compartment, significant deficiencies in B cells (27), NK cells (21, 22), macrophages (15, 20), and dendritic cells (19, 28) have been reported. Despite the abundant evidence that the immune system of the aged is significantly altered, there is mounting data suggesting that some components of the immune system, particularly CD8 T cells, remain functionally intact or are enhanced in old age (11, 26, 34). The characterization of immune responses in the elderly, specifically to pathogens, may lead to more effective vaccination and therapeutic strategies in this highly vulnerable and expanding population.We previously demonstrated that although old mice fail to contain a chronic infection with Mycobacterium tuberculosis (23, 32), during the first 2 weeks following infection, old mice display an enhanced resistance to infection that is gamma interferon (IFN-γ) and CD8 dependent (32, 33). In addition, characterization of in vitro responses of naïve CD8 T cells from old mice to Th1 cytokines identified an interleukin-12 (IL-12)-driven mechanism of enhanced IFN-γ production by these cells (34). Since IL-12 is detected early in the lungs of M. tuberculosis-infected old mice (34), we hypothesized that this same mechanism of innate IFN-γ production was also biologically relevant during M. tuberculosis infection.The aim of the present study was to define and characterize the mechanism by which CD8 T cells contribute to innate immune responses following M. tuberculosis infection. Using both in vivo and in vitro models of M. tuberculosis infection of old mice, we demonstrated that CD8 T cells were a major source of innate IFN-γ. In addition, in vitro assays using purified pulmonary CD8 and CD11c cells from naïve mice conclusively demonstrated that M. tuberculosis-driven IFN-γ production by CD8 T cells from old mice was dependent on IL-12p70 and independent of major histocompatibility complex (MHC)-T-cell receptor interactions. Finally, we provide evidence that suggests that one mechanism by which CD8 T cells from old mice are capable of enhanced innate IFN-γ production is through the regulation of IL-12 signaling.