Background Tuberculosis (TB) is one of the leading causes of death from a single infectious agent with approximately 1.4 million deaths annually. Efforts to eradicate TB are threatened by diabetes mellitus (DM), which confers a greater than a 3-fold TB disease risk. Both TB and DM are accompanied by marked immunologic changes, however, changes in Mtb-specific T-cell functional responses remain poorly characterised. We compared Mtb-specific CD4+ and CD8+ T-cell functional responses among patients with LTBI-DM (21), DM (16), ATB (19) and ATB-DM (04).

Methods Peripheral blood mononuclear cells were stimulated with ESTA-6/CFP-10 peptide pools or PHA, and characterised Mtb-specific CD4+ and CD8+ T cell functional memory (CD45RA/CCR7), activation (HLA-DR), exhaustion (PD-1) and apoptosis (Bcl-2) profiles by flow cytometry. Data were analysed using FlowJo v.10.8.2 and Prism v.8.4.

Results Central memory CD4+/CD8+ T cells were decreased in ATB [median (IQR): 30.80 (20.70–34.80)] compared to DM [41.35(36.63–57.13)] (P<0.0001)/(P=0.0388) and LTBI-DM [45.60(38.75–50.40)] (P<0.0001)/(P=0.0028) patients. Effector memory CD8+ T cells were decreased in DM [21.50(15.18–30.28)] compared to LTBI-DM [32.00(23.45–43.80)] (P=0.0193) patients. TEMRA CD4+ phenotypes were decreased in ATB [1.17(0.88–2.83)] compared to LTBI-DM [0.70(0.30–1.26)] (P=0.0040) and DM [0.99(0.41–1.34)] (P=0.0057) patients. CD4+ T cell HLA-DR expression was upregulated in ATB [2.49(1.12–3.49)] compared to LTBI-DM [1.16(0.89–1.43)] (P=0.0016) and DM [1.63(0.99–2.33)] (P=0.0235) patients. CD4+/CD8+ T cell PD-1 expression was upregulated in LTBI-DM [1.77(1.49–2.94)] compared to DM [1.63(0.95–2.07)] (P=0.0499) and ATB-DM [0.62(0.33–0.94)] (P=0.0381) patients. Finally, CD4+ T cell Bcl-2 expression was increased in ATB [4.17(2.99–5.87)] compared to LTBI-DM [2.08(1.44–3.71)] (P=0.0077) patients.

Conclusion ATB decreases CD4+/CD8+ T-cell central memory while DM decreases CD8+ T-cell effector memory compromising immune surveillance and production of effector cytokines against TB. DM upregulates TEMRA, cells less protective against Mtb. CD4+/CD8+ T cells are exhausted possibly due to persistent inflammation and Mtb-exposure but remain anti-apoptotic. Loss of PD-1 mediated inhibition in DM could promote severe TB disease.