Abstract
BackgroundGranulysin produced by cytolytic T cells directly contributes to immune defense against tuberculosis (TB). We investigated granulysin as a candidate immune marker for childhood and adolescent TB.MethodsPeripheral blood mononuclear cells (PBMC) from children and adolescents (1–17 years) with active TB, latent TB infection (LTBI), nontuberculous mycobacteria (NTM) infection and from uninfected controls were isolated and restimulated in a 7-day restimulation assay. Intracellular staining was then performed to analyze antigen-specific induction of activation markers and cytotoxic proteins, notably, granulysin in CD4+ CD45RO+ memory T cells.ResultsCD4+ CD45RO+ T cells co-expressing granulysin with specificity for Mycobacterium tuberculosis (Mtb) were present in high frequency in TB-experienced children and adolescents. Proliferating memory T cells (CFSElowCD4+CD45RO+) were identified as main source of granulysin and these cells expressed both central and effector memory phenotype. PBMC from study participants after TB drug therapy revealed that granulysin-expressing CD4+ T cells are long-lived, and express several activation and cytotoxicity markers with a proportion of cells being interferon-gamma-positive. In addition, granulysin-expressing T cell lines showed cytolytic activity against Mtb-infected target cells.ConclusionsOur data suggest granulysin expression by CD4+ memory T cells as candidate immune marker for TB infection, notably, in childhood and adolescence.
Highlights
Tuberculosis (TB) remains a leading cause of childhood mortality worldwide with 300,000 cases per year estimated globally and an unequal preponderance in developing countries [1,2,3]
The frequency of CD4+ CD45RO+ T cells in individuals infected with nontuberculous mycobacteria (NTM) and in controls was not changed after stimulation with the recombinant fusion protein ESAT6
A significant induction of granulysin expression in antigen-specific memory T cells was detected for both TB patients (p,0.001) and NTM-infected individuals (p,0.01), but was absent in controls
Summary
Tuberculosis (TB) remains a leading cause of childhood mortality worldwide with 300,000 cases per year estimated globally and an unequal preponderance in developing countries [1,2,3]. Young children are at a much higher risk of progressing to active disease than adults. This is combined with higher mortality, with the highest prevalence among children under 2 years of age and the lowest between 5 and 10 years [4,5]. Most children with active TB are sputum smear negative. Granulysin produced by cytolytic T cells directly contributes to immune defense against tuberculosis (TB). We investigated granulysin as a candidate immune marker for childhood and adolescent TB
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