Research Article: TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection

Date Published: March 11, 2016

Publisher: Public Library of Science

Author(s): Pushpa Jayaraman, Miye K. Jacques, Chen Zhu, Katherine M. Steblenko, Britni L. Stowell, Asaf Madi, Ana C. Anderson, Vijay K. Kuchroo, Samuel M. Behar, David M. Lewinsohn.


While T cell immunity initially limits Mycobacterium tuberculosis infection, why T cell immunity fails to sterilize the infection and allows recrudescence is not clear. One hypothesis is that T cell exhaustion impairs immunity and is detrimental to the outcome of M. tuberculosis infection. Here we provide functional evidence for the development T cell exhaustion during chronic TB. Second, we evaluate the role of the inhibitory receptor T cell immunoglobulin and mucin domain–containing-3 (TIM3) during chronic M. tuberculosis infection. We find that TIM3 expressing T cells accumulate during chronic infection, co-express other inhibitory receptors including PD1, produce less IL-2 and TNF but more IL-10, and are functionally exhausted. Finally, we show that TIM3 blockade restores T cell function and improves bacterial control, particularly in chronically infected susceptible mice. These data show that T cell immunity is suboptimal during chronic M. tuberculosis infection due to T cell exhaustion. Moreover, in chronically infected mice, treatment with anti-TIM3 mAb is an effective therapeutic strategy against tuberculosis.

Partial Text

In countries where tuberculosis exists with a low prevalence, T cell immunity to Mycobacterium tuberculosis enforces latency in 90% of infected people and prevents the development of clinical disease. However, in countries with endemic tuberculosis the cumulative risk for developing active tuberculosis increases with multiple exposures [1]. We hypothesize that chronic antigen stimulation from persistent subclinical infection could induce T cell exhaustion and contribute to the pathogenesis of tuberculosis. T cell exhaustion develops as a step-wise loss of proliferation, cytokine production, and CTL activity during chronic infection caused by HIV, HCV, and HBV; or during cancer [2, 3]. Although the transcriptional signature of dysfunctional CD4+ T cells obtained during chronic viral infection is distinct from that expressed by exhausted CD8+ T cells, exhausted CD4+ and CD8+ T cells also share certain hallmarks that are unique to T cell dysfunction [4]. Specific inhibitory receptors are induced on T cells, which transmit negative signals when they bind ligand. PD1, TIM3, LAG-3, CTLA-4, 2B4, and CD160 are all inhibitory receptors associated with T cell exhaustion [5, 6]. As negative regulators of T cell activity, these molecules prevent over-exuberant inflammation and tissue damage. However, inappropriate inhibitory signaling in tumor-infiltrating lymphocytes during cancer impairs tumor immunity. Importantly, therapeutic blockade of CTLA-4, PD1 or TIM3 reverses T cell exhaustion, improves anti-tumor T cell responses, diminishes tumor size, and increases survival [7–9].

TIM3 is a key negative regulator of T cell function, which has a pathological role in autoimmune diseases, chronic viral infections and malignancies [7, 9, 13, 14, 32–34]. Increased TIM3 expression is observed in people and non-human primates with active tuberculosis, and in this report, we show that TIM3 affects T cell immunity to M. tuberculosis. We find that TIM3 is expressed by two distinct subsets of T cells: 1) T cells that express TIM3 but not other inhibitory receptors (e.g., TIM3+PD1–); and 2) T cells that express TIM3 and other (often multiple) inhibitory receptors (e.g., TIM3+PD1+). TIM3+PD1– T cells produce more IL-2, TNF, and IFNγ, than other cells and share properties with effector T cells (P.J and S.M.B, manuscript in preparation). In contrast, TIM3+PD1+ CD4+ and CD8+ T cells that emerge late during chronic M. tuberculosis infection co-express other inhibitory receptors including Lag-3, produce more inhibitory cytokines (IL-10) and less pro-inflammatory cytokines (IFNγ, TNF and IL-2), and have an in vivo molecular signature that resembles exhausted T cells.




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