Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: Immunity interruptus

Abstract

Despite the introduction almost a century ago of Mycobacterium bovis BCG (BCG), an attenuated form of M. bovis that is used as a vaccine against Mycobacterium tuberculosis, tuberculosis remains a global health threat and kills more than 1.5 million people each year. This is mostly because BCG fails to prevent pulmonary disease – the contagious form of tuberculosis. Although there have been significant advances in understanding how the immune system responds to infection, the qualities that define protective immunity against M. tuberculosis remain poorly characterized. The ability to predict who will maintain control over the infection and who will succumb to clinical disease would revolutionize our approach to surveillance, control, and treatment. Here we review the current understanding of pulmonary T cell responses following M. tuberculosis infection. While infection elicits a strong immune response that contains infection, M. tuberculosis evades eradication. Traditionally, its intracellular lifestyle and alteration of macrophage function are viewed as the dominant mechanisms of evasion. Now we appreciate that chronic inflammation leads to T cell dysfunction. While this may arise as the host balances the goals of bacterial sterilization and avoidance of tissue damage, it is becoming clear that T cell dysfunction impairs host resistance. Defining the mechanisms that lead to T cell dysfunction is crucial as memory T cell responses are likely to be subject to the same subject to the same pressures. Thus, success of T cell based vaccines is predicated on memory T cells avoiding exhaustion while at the same time not promoting overt tissue damage.

Multiple Inflammatory Cytokines Converge To Regulate CD8+ T Cell Expansion and Function during Tuberculosis

“…However, CD8 + T cells appear to be less effective than CD4 + T cells in mediating resistance, despite similar kinetics (28, 35, 42). There are numerous potential signals that modify T cell responses in a diseased lung – soluble mediators and cell surface signals can have both positive and negative effects on T cell expansion and function (43). While it is commonly accepted that optimal CD8 + T cell responses require a third signal – usually mediated by an inflammatory cytokine – how CD8 + T cells are regulated during chronic inflammation is less well understood (13).…”

New Genome-Wide Algorithm Identifies Novel In-Vivo Expressed Mycobacterium Tuberculosis Antigens Inducing Human T-Cell Responses with Classical and Unconventional Cytokine Profiles

“…We have proposed to define the Mtb antigen repertoire expressed in vivo during pulmonary infection. The lung is the primary organ in which Mtb resides and interacts with the human immune system9112122, and where it initiates the process of infection and pathogenesis, setting the stage for future transmission.…”

Chronic Lyme Disease: A Working Case Definition

“…The required duration of chronic illness has ranged from more than three months to more than twelve months (USDHHS, 2010a; Hwang et al, Anderson, 2017; USDHHS, 2010b) and some researchers have suggested that the medical condition needs to be permanent to qualify (Bernstein et al, 2003;McKenna and Collins, 2010). In the setting of infectious disease in general, the term "chronic" often implies a minimum duration of six months, and with chronic Pseudomonas and Mycobacterial infections the chronically infecting pathogens may be capable of "evading or subverting the immune response" to "establish chronic infection with a time course of years to decades, often resulting in persistent inflammation and disease" (Pressler et al, 2011;Behar et al, 2014). In the case of TBDs, this process often becomes established and persists after 3-6 months of untreated or inadequately treated infection (Cameron et al, 2014;.…”