Two billion people carry Tuberculosis (TB). Why do only some get sick?
Review written by: Roshni Kadam
Tuberculosis (TB) remains a major global public health problem, and progress in reducing the burden of disease falls far short of 2030 targets in most parts of the world (World Health Organization, Global Tuberculosis Report 2025). TB is caused by the bacterium Mycobacterium tuberculosis (Mtb), and transmission occurs via aerosolized droplets released by infected individuals. Once inhaled, the droplet nuclei reach the alveoli in the lungs through the nasal and oral cavities. Mtb infection exists in two forms. In latent TB infection (LTBI), the bacteria are contained without clinical disease, and the individual remains asymptomatic and non-infectious. Reactivation leads to active TB disease, which is symptomatic and transmissible. Memory T cells are critical for preventing progression to active disease. Individuals with impaired CD4⁺ T cell responses, most notably people living with HIV, are markedly more susceptible to Mtb infection and progression. Work in CD8⁺ T cells first defined central (T-CM) and effector (T-EM) memory compartments based on tissue homing and effector function. The scheme was later extended by CD27 and CD95 to include stem cell memory (T-SCM) and transitional memory (T-TM) subsets. CD4⁺ T cells have been shown to form similar compartments, but their role in Mtb-specific responses has remained poorly understood. This study therefore characterizes the dynamics of Mtb antigen-responsive memory CD4⁺ T cell subsets, focusing on their metabolic reprogramming and recall function, to provide a basis for designing TB vaccines and for identifying biomarkers of progression risk.
Most people with LTBI contain Mtb indefinitely; a minority progress. To address why, the authors profiled Mtb-responsive CD4⁺ memory subsets in donors with remote LTBI across four levels of evidence: transcript, protein, function, and population. Transcriptional programs were defined by bulk RNA-seq and a targeted 768-gene metabolic panel (Brazil, n=5 and n=3); Met-Flow cytometry (North America, n=3) resolved the corresponding metabolic proteins over 6–72 h; cytokine staining and a macrophage co-culture assay tested Mtb restriction; and deconvolution of an independent longitudinal cohort of Mtb-exposed household contacts with known outcomes (GSE112104) asked whether the same programs distinguished progressors from non-progressors.
Mtb-responsive CD4⁺ memory subsets formed a metabolic gradient from fatty acid oxidation (FAO)-dominant T-SCM to glycolytic T-EM, confirmed at transcript and protein level. Effector function rose along that gradient: T-TM and T-EM produced the most cytokine and best restricted Mtb, but in an independent cohort it was the stem-like, FAO-dominant signature that marked non-progressors, while glycolysis, pentose phosphate pathway activity, and exhaustion marked progressors and TB cases. The central tension is that the subsets best at restricting Mtb in vitro carry the signature of those who fail to contain it in vivo. The authors read this as a trade-off between immediate effector capacity and durable control, and propose that therapies favoring FAO could sustain the functional capacity of CD4⁺ memory T cells in progressors, particularly T-SCM and T-CM. Whether metabolic state drives progression or reflects rising bacterial load remains unresolved.
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READ MORE: Kaipilyawar V, Leong S, Lovey A, Stringari LL, Dietze R, Ellner JJ, Ribeiro-Rodrigues R, Salgame P. Immunometabolic reprogramming of Mycobacterium tuberculosis-responsive memory CD4+ T cell subsets is linked to long-term protective immunity. Front Tuberc. 2026;4:1783887. doi: 10.3389/ftubr.2026.1783887. Epub 2026 Apr 9. PMID: 42368172; PMCID: PMC13299550.
