The Dynamic Change of Immune Checkpoints and CD14+ Monocytes in Latent Tuberculosis Infection

Abstract

Controlling latent tuberculosis infection (LTBI) is important for preventing tuberculosis (TB). However, the immune regulation of LTBI remains uncertain. Immune checkpoints and CD14+ monocytes are pivotal for immune defense but have been scarcely studied in LTBI. We prospectively enrolled participants with LTBI and controls from January 2017 to December 2019. We measured their CD14+ monocytes and the expression of immune checkpoints, including programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and T cell immunoglobulin mucin domain-containing-3 (TIM3) on T lymphocytes in peripheral blood mononuclear cells before and after LTBI treatment. A total of 87 subjects were enrolled, including 29 IGRA-negative healthy controls (HC), 58 in the LTBI group (19 without chronic kidney disease (non-CKD), and 39 with end-stage renal disease (ESRD)). All PD-1, CTLA-4, and TIM3 on lymphocytes and monocytes were higher in the LTBI group than that in the HC group. Total CD14+ monocytes were higher and PD-L2+CD14+ over monocytes were lower in patients with LTBI-non-CKD than that in the HC group. After LTBI treatment, CD14+ monocytes, TIM3+ on CD4+ and monocytes, and CTLA-4 on lymphocytes decreased significantly. Multivariable logistic regression indicated that CD14+ monocytes was an independent factor for LTBI-non-CKD from the HC group, whereas PD-L2+CD14+ monocytes and TIM3+ monocytes were significant for LTBI-ESRD from the HC group. In conclusion, LTBI status was associated with increasing CD14+ monocytes plus low PD-L2 expression. By contrast, increased expression of immune checkpoints over all immune cells might be due to Mycobacterium tuberculosis related immune exhaustion, which decreased after treatment.

Characterization of multiple soluble immune checkpoints in individuals with different Mycobacterium tuberculosis infection status and dynamic changes during anti-tuberculosis treatment

“…In untreated M. tb infection, T cells upregulate the display of multiple co-inhibitory molecules, such as PD-1, TIM-3, LAG-3, reduce production of IFN-γ, secrete suppressive cytokines, and proliferate less, suggesting a suppressive immune status in ATB [ 8 ]. The expression level of co-inhibitory receptors, PD-1, CTLA-4 and TIM-3, on both lymphocytes and monocytes was also found associated with M. tb infection status and changes during LTBI treatment [ 9 ]. Similar changes of circulating sICs levels were found in our ATB and LTBI patients.…”

Risk factors and prognosis for latent tuberculosis infection in dialysis patients: A retrospective cohort study at a single tertiary care center

“…For instance, a study in Norway showed that LTBI was associated with increased serum levels of interleukin 1β, 6, and 22 and tumor necrosis factor α 22 . LTBI status was also associated with higher levels of monocyte/macrophage activation markers and chemo‐tactic mediators, such as CD14, 23 CXCL2, CXCL3, and IL8 24 . Another study reported a subtle increase in circulating interferon γ concentrations in persons with LTBI in the United States, compared with controls without LTBI 25 .…”

Monocyte-to-Lymphocyte Ratio Was an Independent Factor of the Severity of Spinal Tuberculosis

“…The results of Sukson et al showed that MLR was used as a predictor in the diagnosis of tuberculous pleuritis and the AUC was 0.91 [24]. Monocytes promoted the expression level of immune checkpoints and lead to latent tuberculosis infection [25]. MLR may affect the immune response of tuberculosis patients during the process of mycobacterium tuberculosis replication and progression to tuberculosis [26][27][28].…”