Abstract
BackgroundEffector CD4 T cells represent a key component of the host’s anti-tuberculosis immune defense. Successful differentiation and functioning of effector lymphocytes protects the host against severe M. tuberculosis (Mtb) infection. On the other hand, effector T cell differentiation depends on disease severity/activity, as T cell responses are driven by antigenic and inflammatory stimuli released during infection. Thus, tuberculosis (TB) progression and the degree of effector CD4 T cell differentiation are interrelated, but the relationships are complex and not well understood. We have analyzed an association between the degree of Mtb-specific CD4 T cell differentiation and severity/activity of pulmonary TB infection.Methodology/Principal FindingsThe degree of CD4 T cell differentiation was assessed by measuring the percentages of highly differentiated CD27low cells within a population of Mtb- specific CD4 T lymphocytes (“CD27lowIFN-γ+” cells). The percentages of CD27lowIFN-γ+ cells were low in healthy donors (median, 33.1%) and TB contacts (21.8%) but increased in TB patients (47.3%, p<0.0005). Within the group of patients, the percentages of CD27lowIFN-γ+ cells were uniformly high in the lungs (>76%), but varied in blood (12–92%). The major correlate for the accumulation of CD27lowIFN-γ+ cells in blood was lung destruction (r = 0.65, p = 2.7×10−7). A cutoff of 47% of CD27lowIFN-γ+ cells discriminated patients with high and low degree of lung destruction (sensitivity 89%, specificity 74%); a decline in CD27lowIFN-γ+cells following TB therapy correlated with repair and/or reduction of lung destruction (p<0.01).ConclusionsHighly differentiated CD27low Mtb-specific (CD27lowIFN-γ+) CD4 T cells accumulate in the lungs and circulate in the blood of patients with active pulmonary TB. Accumulation of CD27lowIFN-γ+ cells in the blood is associated with lung destruction. The findings indicate that there is no deficiency in CD4 T cell differentiation during TB; evaluation of CD27lowIFN-γ+ cells provides a valuable means to assess TB activity, lung destruction, and tissue repair following TB therapy.
Highlights
Tuberculosis (TB) is one of the most common infectious diseases worldwide
Highly differentiated CD27low M. tuberculosis (Mtb)-specific (CD27lowIFN-c+) CD4 T cells accumulate in the lungs and circulate in the blood of patients with active pulmonary TB
The findings indicate that there is no deficiency in CD4 T cell differentiation during TB; evaluation of CD27lowIFN-c+ cells provides a valuable means to assess TB activity, lung destruction, and tissue repair following TB therapy
Summary
Tuberculosis (TB) is one of the most common infectious diseases worldwide. Prevention of TB dissemination in the community critically depends upon efficient TB diagnostics and treatment. Microbiological diagnosis is limited because patients with less-extensive pulmonary TB often lack identifiable Mtb in their sputum, or sputum is unavailable for microbiological analysis; clinical symptoms are often non-specific; chest radiography does not allow to distinguish between active TB, inactive infection, and other lung pathologies. Such tests should be based on blood sample analysis and should evaluate TB activity, i.e., they should distinguish TB disease from latent infection and assess disease activity in patients with diagnosed TB [1,2,3]. Effector T cell differentiation depends on disease severity/activity, as T cell responses are driven by antigenic and inflammatory stimuli released during infection. We have analyzed an association between the degree of Mtb-specific CD4 T cell differentiation and severity/activity of pulmonary TB infection
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