Accelerating the secondary immune response by inactivating CD4⁺CD25⁺ T regulatory cells prior to BCG vaccination does not enhance protection against tuberculosis

Abstract

CD4+CD25+ natural T regulatory cells (Tregs) have been shown to suppress protective immune responses in several different vaccination models. Since the effect of Tregs on vaccination against tuberculosis (Tb) was unknown, we used a murine model to investigate whether natural Tregs suppress the development of protective immunity following Mycobacterium bovis bacille Calmette‐Guérin (BCG) vaccination. Using a monoclonal antibody against CD25, natural Tregs were inactivated prior to vaccination with BCG. The primary immune response was evaluated after BCG vaccination and the secondary immune response was assessed after an intranasal BCG challenge 42 days after vaccination. Inactivation of natural Tregs prior to vaccination led to an increased immune response 14 days after vaccination, increased numbers of antigen‐responsive lymphocytes immediately prior to secondary challenge and the earlier appearance of IFN‐γ‐producing CD4+ and CD8+ lymphocytes in the draining lymph nodes and lungs after challenge. Despite this, protection from virulent Mycobacterium tuberculosis or M. bovis aerosol challenge was unaffected by natural Treg inactivation prior to BCG vaccination. This suggests that increasing the primary and accelerating the secondary immune responses by inactivating natural Tregs at the time of vaccination, does not affect the development of protective immunity to Tb.

Neither Primary nor Memory Immunity to Mycobacterium tuberculosis Infection Is Compromised in Mice with Chronic Enteric Helminth Infection

“…In a reciprocal experiment, depletion of CD4 ϩ CD25 ϩ Tregs prior to BCG vaccination resulted in enhanced production of IFN-␥ in lymph nodes and lungs following M. tuberculosis challenge. However, this did not translate to better protection against aerosol challenge with M. tuberculosis (43). Together with this study, our finding suggests that Tregs may moderately modulate IFN-␥ responses but without consequence to M. tuberculosis control.…”

Regulatory B and T cells in infections

“…This work shows that functional attenuation of Treg by anti-CD25 mAb (PC61) treatment prior to BCG vaccination increases Th1 responses but not protection against aerosol challenge with virulent M. bovis or M. tuberculosis. The discrepancy with our results could be due to the number of individuals per experimental group and the number of experiments which are not indicated in the study by Quinn et al [18]. Therefore, this work cannot exclude the slight but reproducible fine effect of Treg attenuation in BCG vaccination observed in our study.…”

“…In these experiments, Treg attenuation during BCG immunization has a significant and measurable, albeit moderate, impact on the control of subsequent infection with M. tuberculosis [17]. A similar analysis of anti-mycobacterial T cell immunity and protection against M. tuberculosis subsequent to BCG immunization has been very recently published by Quinn et al [18]. This work shows that functional attenuation of Treg by anti-CD25 mAb (PC61) treatment prior to BCG vaccination increases Th1 responses but not protection against aerosol challenge with virulent M. bovis or M. tuberculosis.…”

Regulatory T Cells Promote Early Influx of CD8+T Cells in the Lungs of Respiratory Syncytial Virus-Infected Mice and Diminish Immunodominance Disparities

“…CD8 ϩ T-cell effector functions and proliferation are often dampened by negative regulation by Treg cells (31, 32). Anti-CD25 antibody depletion studies in the mouse show increased CD8 ϩ T-cell responses following depletion of Treg cells and often increased clearance of the pathogen (8,9,12,29,39,40 [187][188][189][190][191][192][193][194][195] ) responses can be studied simultaneously (19,34,35). This model allows us to look at the relative contribution of epitope-specific CD8 Given the suppressive potential of Treg cells during viral infections, we hypothesized that depletion of Treg cells prior to intranasal infection with RSV would facilitate viral clearance from the lungs yet increase illness due to CD8 ϩ -mediated immunopathology.…”

“…CD8 ϩ T-cell effector functions and proliferation are often dampened by negative regulation by Treg cells (31,32). Anti-CD25 antibody depletion studies in the mouse show increased CD8 ϩ T-cell responses following depletion of Treg cells and often increased clearance of the pathogen (8,9,12,29,39,40).…”