Accumulating evidences have suggested that Treg have an active role in the regulation of immunity to infection. Treg suppress not only autoimmune responses but also other immune responses for instance, during acute infections, against commensal microbes in inflammatory diseases or during chronic illness. Treg have been shown to limit exacerbated inflammation to avoid collateral tissue damage. Treg are also suggested to provide early protective responses in some viral infections as the permitting timely entry of effector cells in infected tissue. Furthermore, Treg have been shown to contribute to form memory pool after resolution of infection. In this review, we survey and analysis our current knowledge and relative dynamics of Treg in a wide range of infection settings and elaborate the examples in which these cells are of critical importance in conferring tolerance, suppressing pathogenesis, inducing protection and optimizing immunity to eliminate infection.
Treg are developmentally and functionally different from conventional T cells. Treg are initially characterized as expressing a CD4+ CD25high phenotype [
A substantial body of evidence has demonstrated an increased recruitment of Treg following infection and accumulation at the sites of infection. For example, Treg have been found to expand in viral infections i.e., hepatitis C [
It has been reported that Treg suppression was associated with the inability of the host to clear Helicobacter pylori infection [
Treg normalize disease intensity associated with virus induced inflammatory lesions. Suvas and co-workers [
Treg check efficient clearance of bacteria during Mycobacterium tuberculosis. Treg-depleted mice infected with M. tuberculosis showed a decreased bacterial burden in the lungs with an elevated pathogen-specific effector T cells [
Treg contribute to pathogen persistence and form a memory pool after resolution of the infection. The latency of Leishmania major in the skin was controlled by the prevalence of Treg [
In West Nile virus infection, Treg maintained a resident memory pool of T cells [
The impact of Treg depletion is time and course of infection dependent. Sawant et al. explored the functional role of Treg following intestinal parasite Trichuris muris infection [
The role of Treg following Salmonella typhimurium infection was demonstrated in which Treg influenced the course of infection [
Treg mediated suppression of CD8 T cells is a significant factor in the consistency of retroviral infections. Dietze and co-workers using DEREG mice showed that transient ablation of Treg following a chronic retroviral infection helps CD8 T cells to recover antiviral potency [
Treg control the mutual host-pathogen interaction during hepatitis C virus infection. Hepatitis C virus was capable of inducing Treg to exert their suppressive potency on effector T cells, and thereby promoted HCV persistence [
In contrast to chronic infections, where excessive number of Tregs leads to pathogen persistence, Tregs in acute infections might aid in limiting immune mediated pathology without delaying viral clearance. For example, in mouse hepatitis virus induced acute encephalitis, Treg play a critical role as their depletion resulted in lethal infection and increased mortality [
There are other acute infection models where Treg have been exhibited to perform a crucial role in limiting immunopathology. For example, in acute pulmonary virus infection by respiratory syncytial virus (RSV), Treg rapidly accumulated in draining LNs and lungs [
There are some evidences of chronic infections in which Treg provide a protective role and help to resolve pathogen clearance. Upon infection with Leishmania panamensis, Treg were presented with a dysregulated phenotype [
We summarize below the data from some of the principal infection systems, with additional details listed in
There is handful of studies in which Treg cross-react with non-pathogenic commensal microbiota in the small and large intestine. Treg are found to suppress microbe-driven intestinal inflammation and Treg repertoire is influenced by the presence of particular commensals or bacterial compounds. For instance, colonization of germ-free mice with commensal microbe altered Schaedler flora (ASF) species resulting in activation and de novo generation of colonic Treg [
Microorganisms | Effect of Treg on immunopathology or pathogen load | Refs |
---|---|---|
Helicobacter pylori | Treg expand in mucosa, CD25 depletion reduces bacterial burden but generates pathology and inflammation. Treg depletion does not influence bacterial colonization or immunopathology | [ |
Herpes simplex virus | Treg ablation generates CD8 T cell response with an efficient viral clearance. Treg depletion associates with exacerbated viral burden in mucosa and nervous system. | [ |
Mycobacterium tuberculosis | Treg depleted mice show decreased bacterial burden in the lungs with pathogen specific effector T cells. Co-transfer of Treg with Th into RAG-1-deficient mice results in suppression of effector CD4 T cells, responsible for protection Pathogen-specific Tregs activated | [ |
Leishmania major | Treg accumulate in the dermis, suppress the ability of effector cells to clear parasite and provide long-term protection from re-infection. | [ |
West nile virus | Treg expand in lymphoid organs and allow memory formation through promoting antigen persistence. Treg-deficient mice have impaired number of memory CD8 T cells | [ |
Trichuris muris | Early Treg depletion accelerates worm clearance with reduced Th1 mediated inflammation. However, the worm titre is augmented when Treg are depleted following infection. | [ |
Salmonella typhimurium | Depletion of Treg early after infection accelerates bacterial eradication. However, depletion during later phase is associated with no significant changes in bacterial clearance. | [ |
Retroviral infection | Transient ablation of Treg following a chronic retroviral infection helps CD8 T cells to recover antiviral potency. | [ |
Friend virus | Depletion of Treg results in a significant increase of FV-specific CD8 T-cell mediated responses which diminishes FV loads in lymphatic organs | [ |
Hepatitis C virus | Hepatitis C virus induces Treg to exert their suppressive potency on effector T cells and promotes HCV persistence | [ |
Respiratory syncytial virus | Treg rapidly accumulates in draining LNs and lungs Depletion of Treg results delayed viral clearance, aggravated disease intensity, including enhanced weight loss, airway restriction and morbidity. Augmented weight loss with delayed recovery following ablation of Treg. | [ |
Leishmania panamensis | Depletion of Tregs results increased parasite load, enlarged lesions, and enhanced production of IL-17 and IFN-γ. Adoptive transfer of Tregs halts disease progression, lowers parasite burden, and reduces cytokine production. | [ |
[
During early life, administration of Clostridium species, a gram positive bacteria,in conventional mice provided resistance to colitis and systemic antibody responses signifying a novel therapeutic approach to autoimmunity. Colonization of mice with Clostridium species from clusters IV, XIVa, and XVIII isolated from human faeces stimulated Treg generation and also increased the production of anti-inflammatory cytokine IL-10 [
Tissue inflammation and autoimmune proliferative response following depletion of Treg were analogous in germ free and conventional mice [
Treg alter antigen-specific immunity and are believed to be responsible for diminished anticancer immune response. Morse and co-workers [
Several studies of infection have indicated that, though the presence of Treg does not participate in disease progression, depletion of Treg results in increased effector responses, supporting pathogen clearance and thus acting as suppressive cell. For example, in H. pylori infection, Treg ablation led to decreased bacterial burden, yet increased gastric inflammation [
However, not all studies have revealed that Treg function to control effector activation. Paradoxically, it has been shown that Treg provide protective responses in some pathogen infections permitting timely entry of effector cells in infected tissue. Although not much appreciated, some of the protective functions of Treg cells are characterized as their depletion resulted in more severe infection. For example, in Mouse Hepatitis Virus induced acute encephalitis, Treg depletion led to lethal infection and resulted increased mortality [
Depletion or reduction of Treg thus augments effective immune responses against pathogenic microbes in most cases while their diminution sometimes reduces effector cell trafficking to the site of infection and might hamper the development of robust secondary immune response following subsequent rechallenge. Also, depletion of Treg in some acute infection models exacerbates disease pathology along with lack of trafficking of effector cells. Hence, Treg providing either suppressive or protective potency over the effector cells either controls or augments the extent of physiological immune response against pathogens and associated immunopathology.
The authors declare no conflict of interest that could be perceived to bias the work.
Rahman, T., Seraj, M.F. and Casellato, A. (2018) Unravelling the Functions of Regulatory T Cells during Infection. Open Journal of Medical Microbiology, 8, 118-131. https://doi.org/10.4236/ojmm.2018.84011
ASF altered Schaedler flora; B. fragilis Bacteroides fragilis; CD Cluster of differentiation; CNS Central Nervous system; DC Dendritic cells; DEREG Depletion of Regulatory T cells; DSS Dextran sulfate sodium; FIV Feline immunodeficiency virus; Foxp3 Forkhead box P3 protein; Foxp3DTR Forkhead box P3 protein-Diphtheria toxin receptor; FV Friend virus; GF mice Germ-free mice; GPR43 G-Protein Coupled Receptor 43; HCV Hepatitis C virus; H. pylori Helicobacter pylori; HSV Herpes Simplex virus; IFN Interferons; IL interleukins; LCMV Lymphocytic Choriomeningitis Virus; LN Lymph nodes; mAb monoclonal antibodies; Mt Mycobacterium tuberculosis; NK Natural killer cells; PSA Polysaccharide A; RAG-1 Recombination activating gene-1; RSV Respiratory Syncytial Virus; SCFA short chain fatty acid; TGFβ Transforming Growth Factor beta; Th T helper cells; TNF Tumour Necrosis factor; Treg CD4+Foxp3+ Regulatory T cell; HIV-1 The human immunodeficiency virus-1.