Association between immunity and antimicrobial treatment resistance in patients with Mycobacterium avium complex pulmonary disease: a multicenter observational study.

BACKGROUND: Mycobacterium avium complex pulmonary disease (MAC-PD) is a refractory infectious disease, with a low success rate of the antimicrobial therapy. T cells and macrophages play a critical role in regulating the mechanism of immunity against mycobacterial infections. Although T cell dysfunction may be associated with treatment failure in MAC-PD, supporting evidence is scarce. This study aimed to elucidate the immunological characteristics of patients with refractory MAC-PD, focusing on immunosuppression and T cell exhaustion. METHODS: Patients with MAC-PD who received standard antimicrobial therapy for at least 12 months were enrolled and classified into treatment success or failure groups. Flow cytometry was used to investigate CD4+ and CD8+ T cell characteristics in peripheral blood mononuclear cells. RESULTS: This study involved 41 patients, including 21 and 20 in the treatment success and failure groups, respectively. Patients with MAC-PD had higher expression of co-inhibitory molecules, including PD-1 and TIM-3, as well as CD160, LAG-3, and 2B4, on CD4+ and CD8+ T cells than healthy controls. However, no differences in expression were observed between the treatment success and failure groups for most activation, co-stimulatory, and co-inhibitory molecules and transcription factors. Furthermore, no difference in effector cytokine production (IL-2, TNF, and IFN-γ) in CD4+ and CD8+ T cells was observed between the groups. However, patients with MAC-PD with low IL-2-producing CD8⁺ T cells had a significantly longer disease duration than those with moderate and high IL-2-producing status (138.3 vs. 42.7 months). CD8+ T cells from patients with MAC-PD with low IL-2 production and prolonged disease duration tended to express higher 2B4 and lower CD28 levels. CONCLUSIONS: The effector functions of CD4+ and CD8+ T cells are not lost during treatment failure. However, low CD8+ T cell IL-2 production was significantly associated with longer disease duration. High 2B4 and low CD28 expression on CD8+ T cells may represent potential markers of T cell dysfunction. Such patients may serve as suitable targets for future host-directed therapies. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Information Network of Japan (registration number: UMIN000043426, registration date: March 1, 2021).