TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection
| Autor: | Chen Zhu, Ana C. Anderson, Katherine Steblenko, Samuel M. Behar, Pushpa Jayaraman, Britni L. Stowell, Vijay K. Kuchroo, Asaf Madi, Miye K. Jacques |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Bacterial Diseases Physiology T-Lymphocytes Immune Receptors Biochemistry Cell-Mediated Immunity Mice White Blood Cells Animal Cells Immune Physiology Medicine and Health Sciences Cytotoxic T cell lcsh:QH301-705.5 Hepatitis A Virus Cellular Receptor 2 Innate Immune System Immune System Proteins biology T Cells Cell Differentiation 3. Good health Interleukin-10 Actinobacteria medicine.anatomical_structure Infectious Diseases Receptors Virus Cytokines Cellular Types Coreceptors medicine.drug Research Article Signal Transduction lcsh:Immunologic diseases. Allergy Interleukin 2 Tuberculosis T cell Immune Cells Immunology Cytotoxic T cells Microbiology Mycobacterium tuberculosis 03 medical and health sciences Immune system Immunity Virology Genetics medicine Animals Humans Molecular Biology Blood Cells Bacteria Organisms Biology and Life Sciences Proteins CD coreceptors Cell Biology Molecular Development medicine.disease biology.organism_classification Tropical Diseases T Cell Receptors Chronic infection 030104 developmental biology lcsh:Biology (General) Immune System Interleukin-2 Parasitology lcsh:RC581-607 Developmental Biology |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 12, Iss 3, p e1005490 (2016) |
| ISSN: | 1553-7374 |
| Popis: | 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. Author Summary Tuberculosis is a leading cause of morbidity and mortality across the globe. Fortunately, most people infected with M. tuberculosis mount a protective immune response and only a small fraction develops active disease. Impairment of immunity late during the course of disease can lead to bacterial recrudescence; however, why immunity fails is poorly understood. We investigated whether T cell exhaustion develops and contributes to immunological impairment during disease. Our studies provide definitive evidence that CD4+ T cells become functionally exhausted early after infection, and subsequently, CD8+ T cells also show signs of dysfunction. T cell exhaustion in both subsets was associated with the expression of multiple inhibitory receptors. Exhausted T cells expressed TIM3 plus other inhibitory receptors (e.g., PD1, TIM3, Lag-3, and 2B4), TIM3+PD1+ T cells were more likely to be poor producers of IL-2, IFNγ, and TNF and instead produce IL-10. Evaluation of gene expression by Nanostring confirmed that TIM3+PD1+ T cells in the lungs of infected mice had a transcriptional profile characteristic of exhausted T cells. Thus, this phenotype identified T cells that were truly exhausted and correlates well with previously established paradigm that co-expression of TIM3 with other inhibitory receptors such as PD1 contributes to impairment of T cell function during chronic inflammatory conditions. Most importantly, treatment of chronically infected mice with blocking antibodies specific for TIM3 led to a significant gain in bacterial control. Treatment was associated with an increase in IL-2, IFNγ, and TNF production by T cells. Based on this key result, we infer that TIM3-mediated T cell exhaustion impairs host resistance to M. tuberculosis. Thus, these data suggest that blockade of inhibitory T cell signals has the potential to be a therapeutic strategy against tuberculosis. The data in our report significantly advances our current knowledge of the biology of TIM3, the role of inhibitory T cell receptors during chronic infection, and the pathogenesis of tuberculosis. |
| Databáze: | OpenAIRE |
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