Rapid Rebound of the Treg Compartment in DEREG Mice Limits the Impact of Treg Depletion on Mycobacterial Burden, but Prevents Autoimmunity

Abstract

The development of an effective vaccine against tuberculosis (Tb) represents one of the major medical challenges of this century. Mycobacterium bovis Bacille Calmette-Guerin (BCG), the only vaccine available at present, is mostly effective at preventing disseminated Tb in children, but shows variable protection against pulmonary Tb, the most common form in adults. The reasons for this poor efficacy are not completely understood, but there is evidence that T regulatory cells (Tregs) might be involved. Similarly, Tregs have been associated with the immunosuppression observed in patients infected with Tb and are therefore believed to play a role in pathogen persistence. Thus, Treg depletion has been postulated as a novel strategy to potentiate M. bovis BCG vaccination on one side, while on the other, employed as a therapeutic approach during chronic Tb infection. Yet since Tregs are critically involved in controlling autoimmune inflammation, elimination of Tregs may therefore also incur the danger of an excessive inflammatory immune response. Thus, understanding the dynamics and function of Tregs during mycobacterial infection is crucial to evaluate the potential of Treg depletion as a medical option. To address this, we depleted Tregs after infection with M. bovis BCG or Mycobacterium tuberculosis (Mtb) using DEREG mice, which express the diphtheria toxin (DT) receptor under the control of the FoxP3 locus, thereby allowing the selective depletion of FoxP3+ Tregs. Our results show that after depletion, the Treg niche is rapidly refilled by a population of DT-insensitive Tregs (diTregs) and bacterial load remains unchanged. On the contrary, impaired rebound of Tregs in DEREG × FoxP3GFP mice improves pathogen burden, but is accompanied by detrimental autoimmune inflammation. Therefore, our study provides the proof-of-principle that, although a high degree of Treg depletion may contribute to the control of mycobacterial infection, it carries the risk of autoimmunity.

Advantages of Foxp3+regulatory T cell depletion using DEREG mice

“…We have previously described that eGFP − Foxp3 + Tregs can be selected by long‐term DT treatment or by certain infections combined with DT treatment of DEREG mice . Similar observations were made with Foxp3.LuciDTR mice undergoing prolonged DT treatment .…”

Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis

“…However, our findings differ from previous AIG studies in several important aspects. First, AIG was not observed in adult C57BL/6 or BALB/c DEREG mice after a similar regimen of Treg cell depletion (42, 44). The different outcomes could be explained by diverse environmental factors as well as differences in the microbiomes, known to influence autoimmune diseases.…”

“…Adult BALB/c DEREG mice crossed with the Foxp3 GFP mice also failed to induce AIG, but blepharitis and scurfy-like auto-inflammation were detected (43). However, unlike the Foxp3 DTR knock-in mice, the adult DEREG mice with transient Treg cell depletion did not succumb to early fatality (42, 44). …”

A weak Foxp3 hypomorph enhances spontaneous and therapeutic immune surveillance of cancer in mice

“…The development of Foxp3 reporters in mice fortuitously generated Foxp3 alleles that are functionally impaired, to various degrees (10)(11)(12)(13). The commonly used Foxp3 fGFP knock-in allele, that encodes a Foxp3 protein fused at its N-terminus to the enhanced green fluorescence protein (eGFP), moderately alters the transcriptional signature and phenotype of Treg, with functional impacts in models of spontaneous autoimmunity and infection (11,12,14). As the Foxp3 fGFP allele does not affect health at steady state in the reference C57Bl/6 (B6) genetic background (12), it is an ideal model to test for specific effect on tumor progression.…”