Host-protective immunity is dependent upon the generation of inflammatory responses that mediate pathogen clearance, but if left unchecked, it can result in excessive tissue pathology. It is now established that distinct T lymphocyte populations serve inflammatory versus suppressive roles, but these functions are often subverted by pathogens that have evolved countermeasures allowing their chronic persistence. In contrast to acute infections that evoke sterilizing immunity, in which infectious organisms are no longer detectable, some chronic infections can result in the persistence of low amounts of infectious particles, as observed in patients infected with the parasites Trypanosoma cruzi or Toxoplasma gondii (1, 2). The low-level persistence of pathogens raises the long-standing debate as to whether immunological memory that protects against reinfection requires T cells to be constantly exposed to Ag or live pathogens. During chronic infections, the long-term persistence of reduced pathogenic loads after a primary infection, despite being protected against secondary exposures, is defined as “concomitant immunity” (3). A similar phenomenon has been described in helminth infections with Schistosoma mansoni and filarial nematodes, in which infection with adult worms provides effective defense against larval stages (4, 5), suggesting that parasites may represent invaluable experimental systems to study these host-pathogen interactions. Whether concomitant immunity emanated from host manipulation by parasites or is a coevolutionary adaptation of host immune responses that strikes a balance between pathogen clearance and tissue immunopathology has remained an important issue since the 1970s.
To address this and other fundamental questions, the experimental mouse model of infection with the obligate intracellular protozoan Leishmania major has been extensively used to investigate the basic tenets of concomitant immunity. Pivotal studies in the late 1980s established that C57BL/6 mice subjected to L. major cutaneous infection develop self-resolving lesions that maintain low-level parasite burdens despite the generation of a robust TH1 response (6, 7). Conversely, L. major infection of BALB/c mice results in metastatic lesions and elevated mortality that are associated with TH2 responses and excessive production of the immunosuppressive cytokine IL-10. Interestingly, human infections with L. major do not reflect such contrasting outcomes, but rather present in a broad spectrum of immunopathologies ranging from individuals that develop strong T cell responses and delayed-type hypersensitivity reactions to patients with elevated Ab titers who are unable to control parasite burdens (8, 9). Nonetheless, it is well documented that exposure to viable parasites in a specific skin location, a process referred as “leishmanization”’ (10), is highly effective in protecting against natural infections, suggesting that concomitant immunity can develop in L. major–infected patients. Together, these findings have motivated studies of the complex dialog stemming from low parasite levels and host immune responses.
Groundbreaking studies by Belkaid et al. in this Pillars of Immunology article (https://doi.org/10.1038/nature01152) demonstrated that, along with IFN-γ–producing CD4+ T effector (Teff) cells, skin lesions in L-major–infected C57BL/6 mice were enriched with a subset of IL-10–secreting CD4+ T cells. This cell subset also expressed high levels of the IL-2 receptor α-chain (also known as CD25) and CTLA-4, and potently suppressed the proliferation of Teff cells (11). Demonstration that this T regulatory (Treg) cell subset expanded during chronic cutaneous leishmaniasis provoked a number of fundamental questions, many of which remain to this day. One issue was whether Treg cells constituted an evolutionary trade-off between host fitness and parasite survival. It is tempting to propose that leishmania-induced Treg cells mainly function to hold infection-induced inflammation in check, preventing a complete loss of tissue integrity that could lead to secondary bacterial infections, sepsis, and death. Of course, the trade-off to holding inflammation in check is that it favors pathogen persistence. Whether such Darwinian selection emanated from the host or pathogen remains an unanswered question. Perhaps a host-selective process is implicated because IL-10 is central to the mechanism of concomitant immunity. Indeed, Belkaid and colleagues demonstrated that IL-10–deficient mice efficiently cleared all the parasites in the lesion site but with no significant changes in its size (12), suggesting that modulation by leishmania-induced Treg cells may have other effects on disease outcome. Since this work was published, we have now gained a better understanding of the multiple mechanisms by which Treg cells operate including TGF-β and IL-35 secretion, cell-contact molecules such as CTLA-4 and LAG-3, as well as metabolic disruption through IL-2 deprivation and release of adenosine nucleosides (13). As such, it is likely that Treg cells operate via several molecular pathways, and the contribution of these to the outcome of cutaneous leishmaniasis should be further evaluated.
At the time that the studies by Belkaid et al. were published, Treg cells were proposed to suppress the activity of autoreactive Teff cells, leading most to consider that their TCR repertoire recognizes various self-antigens (14). However, the epitope specificity of leishmania-induced Treg cells remained elusive. It is now recognized that Treg cells can be derived from the thymus (tTregs) or induced in the periphery (14). Although this Pillars of Immunology article demonstrates that leishmania-induced Treg cells can be recruited from a pre-existing pool in naive mice (11), it is not clear whether leishmania parasites promote the expansion of thymic Tregs that are cross-reactive to parasite-derived Ags or if leishmania manipulates the tissue microenvironment to induce the differentiation of peripheral Tregs. Alternatively, tissue damage that occurs at the lesion site may result in the release of self-antigens that activate tTregs; considering that skin Treg cells have been shown to facilitate wound healing (15). Furthermore, it is clear now that Treg cells can be further subdivided based on their expression of other transcription factors such as GATA-3 and RORγT, each subset associated with specific functions (16), but how this heterogeneity translates to the regulatory landscape induced in cutaneous leishmaniasis remains to be investigated. This picture becomes even more complex considering the mounting evidence that the tissue-specific properties of skin-resident Treg cells are influenced by skin microbiota, environmental factors, and hair follicle–derived signals (16). Therefore, it is possible that the contribution of Treg cells to the generation of concomitant immunity against cutaneous leishmaniasis represents a unique process that occurs in the skin.
Remarkably, the findings of this Pillars of Immunology article not only challenged the dogma that sterilizing immunity is required to generate immune memory, but they also demonstrated that IL-10 and potentially Treg cells are necessary to develop resistance against reinfection with L. major (11). On one hand, it can be argued that the low numbers of parasites may function as a persistent source of Ags that is required to maintain a pool of memory T cells. However, long-lived central memory T cells have been shown to survive in the absence of persistent parasite load (9). Alternatively, Treg cells might contribute to the generation of memory T cells via their secretion of IL-10, which has been demonstrated to promote the maturation of memory CD8+ T cells (17, 18). Furthermore, it has become clear that skin-resident memory CD4+ T cells (TRM) are central for protection against L. major (19). Therefore, whether coordination between skin-resident Treg and skin-resident memory CD4+ T cells is required for concomitant immunity against cutaneous leishmaniasis needs further investigation. More importantly, understanding the contributions of Treg cells to the development of protective immunity would aid vaccine efforts to combat acute and chronic infections. Particularly now, amid the COVID-19 pandemic, we urgently need to understand the basic mechanisms responsible for the efficacy of SARS-CoV-2 vaccines. Studies focused on understanding how Treg cells facilitate protective immunity could provide critical insight(s) into the controversy over whether naturally infected or vaccinated individuals can develop long-term immunity (>1 y). Although there are still a number of questions to be addressed, this Pillars of Immunology article set the stage for an explosion of interest in Treg cell biology in the context of chronic infections that persists today.
Footnotes
This work was supported by Grant U01-AI125940 from the National Institutes of Health.
References
Disclosures
The authors have no financial conflicts of interest.