Altered monocyte phenotypes but not impaired peripheral T cell immunity may explain susceptibility of the elderly to develop tuberculosis

Abstract

Tuberculosis (TB) is the leading killer due to a single infectious disease worldwide. With the aging of the global population, the case rate and deaths due to TB are highest in the elderly population. While general immunosenescence associated with old age is thought to contribute to the susceptibility of the elderly to develop active TB disease, very few studies of immune function in elderly individuals with Mycobacterium tuberculosis (M.tb) infection or disease have been performed. In particular, impaired adaptive T cell immunity to M.tb is one proposed mechanism for the elderly's increased susceptibility primarily on the basis of the decreased delayed type hypersensitivity response to tuberculin-purified protein derivative in the skin of elderly individuals. To investigate immunological reasons why the elderly are susceptible to develop active TB disease, we performed a cross-sectional observational study over a five year period (2012-2016) enrolling participants from 2 age groups (adults: 25-44 years; elderly: 65 and older) and 3 M.tb infection statuses (active TB, latent TB infection, and healthy controls without history of M.tb infection). We hypothesized that impaired peripheral T cell immunity plays a role in the biological susceptibility of the elderly to TB. Contrary to our hypothesis, we observed no evidence of impaired M.tb specific T cell frequency or altered production of cytokines implicated in M.tb control (IFN-γ, IL-10) in peripheral blood in the elderly. Instead, we observed alterations in monocyte proportion and phenotype with age and M.tb infection that suggest their potential role in the susceptibility of the elderly to develop active TB. Our results suggest a potential link between the known widespread low-grade systemic inflammation of old age, termed "inflammaging," with the elderly's specific susceptibility to developing active TB. Moreover, our results highlight the need for further research into the biological reasons why the elderly are more susceptible to disease and death from TB, so that public health systems can be better equipped to face the present and future problem of TB in an aging global population.

Keywords: Geriatrics; Immunosenescence; Inflammaging; Monocyte; T cell; Tuberculosis.

Figure 1. T cell cytokine responses to M.tb antigens are not altered by age in those with LTBI or active TB

Number of IFN-γ+ T cells, measured in spot forming units (SFUs), responding to ESAT-6 (A) and CFP-10 (B) from M.tb. IFN-γ (C) and IL-10 (D) from culture supernatants of PBMCs stimulated with M.tb culture filtrate protein. Boxplots are medians with interquartile ranges. Total subjects for each panel are 157 (A), 157 (B), 100 (C) and 164 (D). ** p<0.01 by Mann-Whitney U test.

Figure 2. Global T cell CCR7 phenotype is not altered by age in those with LTBI or active TB but PD-1 phenotype may be increased in elderly with active TB

Percent of CD4+ (A) and CD8+ (B) lymphocytes expressing CCR7. Percent of CD4+ (C) and CD8+ (D) lymphocytes expressing PD-1. For all comparisons between age groups not displayed, there were no significant differences (p>0.05). Boxplots are medians with interquartile ranges. Total subjects for each panel are 135 (A), 134 (B), 143 (C) and 142 (D). Other Kruskal-Wallis p values were p=0.0001 (B) and p=0.03 (C). * p<0.05, ** p<0.01, ***p<0.001 by Dunn’s test.

Figure 3. Monocyte/lymphocyte ratio is increased in elderly with active TB and decreased in elderly with LTBI, and old age and M.tb infection skew monocytes towards a nonclassical phenotype

Monocyte/lymphocyte ratio (A) and percent monocytes with nonclassical (CD14dimCD16+) phenotype (B). Boxplots are medians with interquartile ranges. Total subjects for each panel are 91 (A) and 91 (B). Kruskal-Wallis p values were p=0.002 (A) and p=0.003 (B). * p<0.05, ** p<0.01, ***p<0.001 by Dunn’s test, or p value otherwise displayed.