Tissue Associated Tregs May Explain Why Some Children Have Persistent Ear Infections

Maybe you know a small child who just can’t seem to shake an ear infection. Maybe, at one time, you were that child. There is good news; immunologists may be one step closer to understanding why the infection is sticking around.

Streptococcus pneumoniae (pneumococcus) is a harmful bacterium that causes millions of deaths every year. Pneumonia, meningitis, and ear infections (otitis media) are all the handiwork of this bacterium. Young children often carry pneumococcus until age three. By that time, their adaptive immune response (not the primary line of defense but the very specific, memory based line of defense) either prevents the infection or quickly removes it with the help of the immune cells in the NALT (nasal-associated lymphoid tissue).

It is curious, then, how some children who display immunological memory for the pathogen continue to carry the infection in their nasopharynx. A recent study Zhang et. al. in PLoS Pathogens suggests that regulatory T cells (Tregs) may be responsible for allowing the infection to persist.

The job of Tregs is to prevent the immune system from creating so vigorous a response against a pathogen that it damages the body. Tregs also help to keep the immune system from attacking the body itself (preventing autoimmunity). Tregs are the policing cells of the immune system. While they are providing a helpful service by protecting the body, their conservative behavior makes it easier for infections to persist.

Tregs are developed from naïve T cells that have received a signal telling them become policing cells. They then display certain molecules in their interior and on their surfaces that allow them to act and be identified and as Tregs. Among these markers are Foxp3 and CTLA-4, in the cell interior, and CD39 and CD25, on the cell surface. (A CD is a “cluster of differentiation” and can be thought of as an identification tag for immune cells). For example Foxp3^high CD25^high Tregs are of the “effecter/memory type” and may be responsible for the inability to clear pathogens like pneumococcus.

Zhang and coworkers investigated the prevalence of Tregs in the adenoids and the effect they had on CD4+ T cells, an immune cell that works to clear infections by assisting other cells. (Even though pneumococcus is a bacterium, and B cells and their antibodies usually deal with bacteria, recent studies suggest that CD4+ T cells are also key players in the fight against pneumococcus (2). In fact, part of what makes this study unique is its investigation of the effects of Tregs on CD4+T cells specifically).

To conduct their study, Zhang et. al. examined adenoidal and peripheral blood collected from pneumococcal-infected and -uninfected children. They found a higher population of effecter/memory Tregs in adenoidal blood than in peripheral blood. In other words, there were more Tregs in the adenoids than the rest of the body. They also discovered that children carrying pneumococcus had a higher population of Tregs in the adenoids than children without pneumococcus. These Tregs were also more potent, expressing more CD39 and CTLA-4 than Tregs from uninfected children. These results suggest that pneumococcus itself may be responsible for the production of Tregs. They hypothesize that upon some pneumococcal signal, Tregs develop in the secondary tissues as opposed to in the thymus, as is typical. This result is similar to findings in studies of HIV and Tuberculosis (TB), where the presence of these infections increased the local concentrations of Tregs (3). Thus this result adds to the evidence that these pathogens are manipulating Treg concentrations to their own advantage.

When the researchers infected adenoidal blood with pneumococcus, the number of Tregs present increased. When adenoidal blood was infected with pneumococcus in the absence of Tregs, CD4+ T cells were found to proliferate profusely. Furthermore the CD4+ T cells released cytokines, small signaling molecules, one of which, IL-17 helps neutrophils, another type of immune cell, to phagocytose (kill and digest) pneumococcus (4). When the Tregs were reintroduced, the proliferation was suppressed and IL-17 was no longer produced, suggesting that Tregs are inhibiting pneumococcal clearing.

The authors are unsure how pneumococcus stimulates Tregs to accumulate in the adenoids. They suggest that pneumococcal proteins could be responsible, because when a proteinase (molecule that cuts up proteins) was introduced, more CD4+ T cells were produced. Understanding the exact mechanism remains a potent area of further study. Findings have the potential to help millions of people, not only those plagued by pneumococcus, but also those infected with HIV and TB, all of which increase the amount of Tregs present in local tissues and prevent the clearing of the infections.

Reference:

Zhang, Q., Leong, S.C., McNamara, P.S., Mubarak, A., Malley, R., et. al. (2011). Characterisation of Regulatory T Cells in Nasal Associated Lymphoid Tissue in Children: Relationships with Pneumococcal Colonization. PLoS Pathog. 7(8): e1002175.

Other Citations:

2. Malley, R., Trzcinski, K., Srivastava, A., Tompson, C.M., Anderson, P.W., et. al. (2005). CD4+ T cells mediate antibody-independent acquired immunity to pneumococcal colonization. Proc. Natl. Acad. Sci. USA 102: 4848 - 4853.

3. Anderson, J., Boasso, A., Nilsson, J., Zhang, R., Shire, N.J., et. al. (2005). The prevalence of regulatory T cells in lymphoid tissues is correlated with viral load in HIV-infected patients. J. Immunol. 174: 3143 – 3147.

4. Lu, Y.J., Gross, J., Bogaert, D., Finn, A., Bagrade, L., et. al. (2008). Interleukin-17A mediates acquired immunity to pneumococcal colonization. PLoS Pathog. 4: e1000159.