Effect of bacillus Calmette-Guérin vaccination on CD4+Foxp3+ T cells during acquired immune response to Mycobacterium tuberculosis infection

Abstract

Increasing information has shown that many newly emerging strains of Mycobacterium tuberculosis, including the highly prevalent and troublesome Beijing family of strains, can potently induce the emergence of Foxp3(+)CD4 Tregs Although the significance of this is still not fully understood, we have previously provided evidence that the emergence of this population can significantly ablate the protective effect of BCG vaccination, causing progressive fatal disease in the mouse model. However, whether the purpose of this response is to control inflammation or to directly dampen the acquired immune response is still unclear. In the present study, we have shown, using both cell depletion and adoptive transfer strategies, that Tregs can have either properties. Cell depletion resulted in a rapid, but transient, decrease in the lung bacterial load, suggesting release or temporary re-expansion of effector immunity. Transfer of Tregs into Rag2(-/-)or marked congenic mice worsened the disease course and depressed cellular influx of effector T cells into the lungs. Tregs from infected donors seemed to preferentially depress the inflammatory response and granulocytic influx. In contrast, those from BCG-vaccinated and then challenged donors seemed more focused on depression of acquired immunity. These qualitative differences might be related to increasing knowledge reflecting the plasticity of the Treg response.

Biology of clinical strains of Mycobacterium tuberculosis with varying levels of transmission

“…This adds a further variable, namely the environment in which the isolates become spread. For instance, isolates obtained [ 40 ] in the Bay Area [California] are transmitted amongst a [mostly Chinese] population in which nutrition is good and HIV rates low, and so these isolates seem to have evolved the capacity to generate regulatory T cell activity – which we now know can directly target acquired protective immunity [ 41 ] -- in order to survive and persist. In the Western Cape there is malnutrition and high rates of HIV, so regulatory T cell responses are not a factor and the [admittedly limited] strains we have tested so far do not induce them to any extent.…”

The double‐edged sword of Tregs in M tuberculosis, M avium, and M. abscessus infection

“…The cytokines produced by Th1 cells are interferonγ, IL-2, TNFα producers. 23 In contrast, Th2 produces the signature cytokines IL-4, IL-5, and IL-13. The Th1/Th2 can have negative regulatory feedback limiting each other's ability to expand and execute an effort function.…”

“…These cells are classified by the effector cytokines they produce and the expression of different clusters of differentiation markers (CD) and additional transcription factors. The cytokines produced by Th1 cells are interferon‐γ, IL‐2, TNF‐α producers 23 . In contrast, Th2 produces the signature cytokines IL‐4, IL‐5, and IL‐13.…”

Pulmonale Immunität bei Tuberkulose

“…In Ex-vivo-Infektionsexperimenten mit alveolären Mφ und Mtb führte die Zugabe von T regs aus dem Blut des gleichen Probanden zu vermehrten mykobakteriellen Wachstumsraten [37]. Dies ließ sich auch in vivo im Mausmodell für pulmonale T regs nachvollziehen, was den Schluss nahelegt, dass pulmonale T regs funktional aktiv sind und nicht nur "in Rufbereitschaft" (Bystander) in die Lunge rekrutiert werden, um gewebezerstörende Immunreaktionen einzudämmen [38]. Nach derzeitigem Verständnis schwächen funktional aktive T regs somit die Immunantwort in der Lunge, was zu vermehrtem bakteriellen Wachstum führt und ggf.…”