Mtb is an intracellular bacteria, and therefore researchers studying the immune response to it have mainly focused their attention on CD4⁺ T cells, which specialize in recognizing infected innate immune cells and secrete a variety of cytokines that attract other immune cells to the site of infection. However, growing evidence suggests that CD8⁺ T cells, which had been thought to become involved in the infection in killing target cells, also play a role in battling Mtb early on. The study found that CD8⁺ T cells arrived first in the granulomas, becoming detectable at the 12-week timepoint. CD4⁺ T cells only appeared after 20 weeks. “We know that CD4 [T cells] are important; everybody knows that. But in our parameters, there wasn’t a significant difference in the frequency of those cells until the late time point,” Flynn says.  

To gain more information on those T cells, the researchers profiled the expression of transcription factors that reflect immune cell function. Among the transcription factors analyzed, they found that one called T-Bet stood out for its increased expression over the course of infection, first author Nicole Grant tells The Scientist. T-Bet is a pro-inflammatory transcription factor known for its involvement in immune responses to pathogens; previous studies have found that the presence of T cells expressing T-Bet is associated with control of infectious diseases, including TB.  

In the new study, the researchers saw that there is an increase in the frequency of T-Bet expression in CD8⁺ T cells found within the granulomas at 12 weeks, followed by an increased frequency of CD4⁺T-Bet⁺ cells at 20 weeks postinfection. The appearance of T-Bet⁺ T cells corresponded to a reduction of the bacterial burden, further confirming the importance of T-Bet-expressing cells in granulomas.   

The researchers hypothesize that the slow evolution of adaptive immunity contributes to the ease with which Mtb establishes infection and supports the development of latent disease. “Even if it doesn’t tell you the mechanism, you see the bacteria go down in this study” when T cell frequency increase, explains Leslie. “This agrees with all the literature that the bugs have more difficulty once the adaptive immune response turns up. [It] all make perfect biological sense.” Neil Schluger, a tuberculosis researcher at Columbia University who was not involved in the study, says the study used an appropriate model system to reach sophisticated findings on the adaptive immune response at the site of the granulomas and its evolution over time, adding to researchers’ knowledge of the complicated human host response to TB. 

Flynn says she hopes that “our results can inform vaccine design.” The current vaccine for TB, BCG (Bacillus Calmette-Guérin), is 70 to 80 percent effective against the most severe forms of TB, but is less effective in preventing the form of the disease that affects the lungs. “The development of good vaccines has been challenging for two main reasons that this paper addresses: the lack of using good animal models and the lack of deeper understanding of the immune response,” Schluger tells The Scientist. The authors write in their paper that the results suggest using a vaccine to enhance T-Bet specific CD8⁺ T cell responses together with CD4⁺ T cell responses could improve protection against infection and progressive disease. “Even though it is a descriptive study, most good science begins with an observation, and this study is a reminder of that,” says Schluger.