Biology subjects

Montes, C. L.

Publications and source records attributed to Montes, C. L..

10 recordsLinked to original sources

bioRxiv2026

Distinct profiles and antibody production by splenic and lymph node antibody-secreting cells in Trypanosoma cruzi infection

Evidence from bone marrow and intestinal lamina propria studies indicates that antibody-secreting cell (ASC) characteristics are shaped by the local microenvironment; yet whether secondary lymphoid organs harbor distinct ASC populations during infection remains unclear. Here, we investigated plasmablasts (PB) from the spleen and inguinal lymph nodes (LN) in acute Trypanosoma cruzi infection. Although PB from both tissues expressed canonical ASC markers, they displayed distinct transcriptional, phenotypic, and functional profiles. Splenic PB upregulated genes and proteins associated with inflammation, immunomodulation, and B-cell interactions. Activated and naive B cells also exhibited tissue-specific transcriptional programs, suggesting that local cues influence B-cell differentiation. Consistent with these differences, spleens from infected mice contained more T follicular helper cells, whereas LN were enriched in regulatory T cells. High-dimensional flow cytometry identified multiple PB subsets differentially represented between tissues. Functionally, splenic PB secreted higher levels of IgM, IgA, and IgG, including both parasite-specific and autoreactive antibodies. In contrast, LN PB preferentially produced IgG against peptide 72 of the shed acute-phase antigen (SAPA), despite lower overall T. cruzi-specific antibody production. These findings demonstrate that secondary lymphoid organs harbor distinct PB populations adapted to their local microenvironments during acute infection

immunology↗

bioRxiv2026

Dual Th1 and tissue-repair Treg cells accumulate in skeletal muscle preserving tissue integrity during infection

Chronic infections require mechanisms that limit tissue damage while preserving pathogen control, yet the contribution of regulatory T (Treg) cells to this balance remains unclear. In this study, we characterized Treg cell responses during a chronic parasitic infection using experimental Trypanosoma cruzi infection as a model of persistent low-level parasitism and chronic tissue inflammation. We found that, although Treg cell numbers decline in the spleen, they accumulate in parasite-affected tissues such as skeletal muscle, where they adopt a combined Th1-associated and tissue-repair program. Systemic Treg cell depletion had limited impact on immune and disease-associated parameters, whereas local depletion in skeletal muscle exacerbated tissue damage and increased parasite burden. Moreover, transient systemic perturbation of Treg cells during the acute phase impaired their long-term accumulation in skeletal muscle, resulting in increased tissue damage and parasite burden during chronic infection. Additionally, accumulation of reparative Treg cells in skeletal muscle was impaired in the absence of ST2. Together, these findings identify a tissue-adapted Treg cell population that integrates inflammatory and reparative programs to preserve skeletal muscle integrity during chronic parasitic infection. SUMMARYChronic parasite infection drives the emergence of tissue-adapted regulatory T cells that integrate Th1-associated and tissue-repair programs. These cells accumulate in skeletal muscle, where they preserve tissue integrity while contributing to microbial control, highlighting the dynamic specialization of Treg cells across disease stages.

immunology↗

bioRxiv2026

Tissue-distinct Features of Follicular Cytotoxic CD8+ T Cells in Trypanosoma cruzi infection

T follicular cytotoxic (Tfc) cells are a specialized subset of CD8 T lymphocytes that combine helper and cytotoxic functions. While their phenotypic and functional properties have been described in several infectious and inflammatory settings, little is known whether Tfc cells exhibit distinct characteristics across secondary lymphoid organs. Using acute Trypanosoma cruzi infection as a model of systemic immune activation, we performed a comparative phenotypic, transcriptomic, metabolic, and functional characterization of Tfc cells arising in the spleen and inguinal lymph nodes. Tfc cells emerged transiently in both organs with similar kinetics and antigen specificity yet segregated primarily according to tissue of analysis at the transcriptional level. Splenic Tfc cells exhibited enhanced glycolytic and mTORC1-associated signatures, increased mitochondrial mass, and stronger cytotoxic and B cell helper functions, promoting immunoglobulin production and plasmablast death. In contrast, Tfc cells from lymph node preferentially displayed memory-associated features, including higher CD127 and CD122 expression, increased IL-2 production, and preferential persistence during chronic infection. Together, these findings demonstrate that Tfc cells are not a homogeneous population but can adopt organ-associated transcriptional, metabolic, and functional states during T. cruzi infection.

immunology↗

bioRxiv2024

Tissue damage during acute Trypanosoma cruzi infection is associated with reduced reparative regulatory T cell response and can be attenuated by early interleukin-33 administration.

Tissue-repair regulatory T cells (trTregs) constitute a specialized regulatory subset renowned for orchestrating tissue homeostasis and repair. While extensively investigated in sterile injury models, their role in infection-induced tissue damage and the regulation of protective antimicrobial immunity remains largely unexplored. This investigation examines trTregs dynamics during acute Trypanosoma cruzi infection, a unique scenario combining extensive tissue damage with robust antiparasitic CD8+ immunity. Contrary to conventional models of sterile injury, our findings reveal a pronounced reduction of trTregs in secondary lymphoid organs and tissues during acute T. cruzi infection. This unexpected decline correlates with systemic as well local tissue damage, as evidenced by histological alterations and downregulation of repair-associated genes in skeletal muscle. Remarkably, a parallel decrease in systemic levels of IL-33, a crucial factor for trTregs survival and expansion, was detected. We found that early treatment with systemic recombinant IL-33 during infection induces a notable surge in trTregs, accompanied by an expansion of type 2 innate lymphoid cells and parasite-specific CD8+ cells. This intervention results in a mitigated tissue damage profile and reduced parasite burden in infected mice. These findings shed light on trTregs biology during infection-induced injury and demonstrate the feasibility of enhancing a specialized Tregs response without impairing the magnitude of effector immune mechanisms, ultimately benefiting the host. Furthermore, this study settles groundwork of relevance for potential therapeutic strategies in Chagas disease and other infections. AUTHOR SUMMARYChagas disease, caused by the protozoan Trypanosoma cruzi, induces severe organ damage caused by the interplay between the parasite and the immune response. In our investigation, we delved into the role of tissue-repair regulatory T cells (trTregs) during the acute phase of T. cruzi infection in mice. Surprisingly, we observed a reduction in trTregs during the peak of tissue damage, contrary to their usual accumulation after injury in other contexts. This decline aligned with decreased levels of interleukin-33, a critical factor for trTregs survival. Administering interleukin-33 at early infection times not only boosted trTregs but also expanded other reparative and antiparasitic immune cells. Consequently, these treated mice exhibited reduced damage and lower parasite levels in tissues. Our findings offer insights into trTregs behavior during infection-induced injury, suggesting a promising avenue for therapeutic interventions in Chagas disease and related conditions. This study lays the groundwork for potential strategies that balance the immune response, supporting tissue repair without compromising the ability to control the infection, which could have broader implications for infectious diseases and tissue damage-related pathologies.

immunology↗

bioRxiv2023

CD39 expression by regulatory T cells drives CD8+ T cell suppression during experimental Trypanosoma cruzi infection

An imbalance between suppressor and effector immune responses may preclude cure in chronic parasitic diseases. In the case of Trypanosoma cruzi infection, specialized regulatory Foxp3+ T (Treg) cells suppress protective type-1 effector responses. Herein, we investigated the kinetics and underlying mechanisms behind the regulation of protective parasite-specific CD8+ T cell immunity during acute T. cruzi infection. Using the DEREG mouse model, we found that Treg cells play a critical role during the initial stages after T. cruzi infection, subsequently influencing CD8+ T cells. Early Treg cell depletion increased the frequencies of polyfunctional short-lived, effector T cell subsets, without affecting memory precursor cell formation or the expression of activation markers. In addition, Treg cell depletion during early infection minimally affected the antigen-presenting cell response but it boosted CD4+ T cell responses before the development of anti-parasite effector CD8+ T cell responses. Crucially, the absence of CD39 expression on Treg cells significantly bolstered effector parasite-specific CD8+ T cell responses, leading to improved parasite control during T. cruzi infection. Our work underscores the crucial role of Treg cells in regulating protective anti-parasite immunity and provides evidence that CD39 expression by Treg cells represents a key immunomodulatory mechanism in this infection model.

immunology↗

bioRxiv2023

CD39+ conventional CD4+ T cells with exhaustion traits and cytotoxic potential infiltrate tumors and expand upon CTLA-4 blockade

BackgroundConventional CD4+ T (Tconv) lymphocytes play important roles in tumor immunity; however, their contribution to tumor elimination remains poorly understood. MethodsHere we describe a subset of Tconv cells characterized by the expression of CD39. The phenotype, the effector function and transcriptional profile of tumor-infiltrating CD39+ Tconv lymphocytes from different mouse cancer models and breast cancer patients were studied by multiparametric flow cytometry and RNA sequencing. The impact of the in vivo CTLA-4 blockade on the tumor-infiltrating CD39+ Tconv population was assessed in mice grafted with the immunogenic MC38 colorectal tumor. Overall survival was evaluated in a cohort of patients from the TCGA consortium. ResultsIn mouse cancer models, we observed that CD39+ Tconv cells accumulated in tumors as they grew but were absent in lymphoid organs. Compared to tumor CD39- counterparts, CD39+ Tconv cells exhibited a cytotoxic and exhausted signature at the transcriptomic level, confirmed by high protein expression of inhibitory receptors and transcription factors related to the exhaustion phenotype. Additionally, CD39+ Tconv cells showed increased production of IFN gamma, granzyme B, perforin and CD107a expression, but reduced production of TNF. In vivo CTLA-4 blockade induced the expansion of tumor CD39+ Tconv cells, which maintained their cytotoxic and exhausted features. In breast cancer patients, CD39+ Tconv cells were found in tumors and in metastatic lymph nodes but were less frequent in adjacent non-tumoral mammary tissue and not detected in non-metastatic lymph nodes and blood. Human tumor CD39+ Tconv cells constituted a heterogeneous cell population with features of exhaustion, impaired TNF production, and high expression of inhibitory receptors and CD107a. We found that high CD4 and ENTPD1 (CD39) gene expression in human tumor tissues correlated with a higher overall survival rate in breast cancer patients. ConclusionsWe found that CD39 acts as a biomarker of Tconv cells with characteristics of both exhaustion and cytotoxic potential. CTLA-4 blockade expands CD39+CD4+ T cells which may contribute to the reduction of tumor development. Discovering the role of CD39-expressing CD4+ T cells in the tumor microenvironment should help design new strategies to manipulate them and improve the efficacy of current immunotherapies.

immunology↗

bioRxiv2022

Interleukin-17 signaling influences CD8+ T cell immunity and tumor progression according to the IL-17 receptor subunit expression pattern in cancer cells

The role of IL-17 mediated immune responses in cancer is conflicting as pre-clinical and clinical results show tumor-promoting as wel as tumor-repressing functions. Herein, we used syngeneic tumor models from different tissue origins as a tool to evaluate the role of IL-17 signaling in cancer progression, dissecting the effects in cancer cell growth and tumor immunity. We show that absence of IL-17RA or IL-17A/F expression in the host has contrasting effects in the in vivo growth of different tumor types. We observed that lack of IL-17A/F-IL-17RA signaling in host cells changed the expression pattern of several mediators within the tumor microenvironment in a cancer-type specific manner. Deficiencies in host IL-17RA or IL-17A/F expression resulted in reduced antitumor CD8+ T cell immunity in all cancer models and in tumor-specific changes in several lymphoid cell populations. These findings were associated to particular patterns of expression of cytokines (IL-17A and IL-17F) and receptor subunits (IL-17RA, IL-17RC and IL-17RD) of the IL-17 family in the injected tumor cell lines that, in turn, dictated tumor cell responsiveness to IL-17. We identified IL-17RC as an important determinant of the IL-17-mediated transcriptional response in tumor cells and; consequently, as a predictive biomarker of the overall effect of IL-17 signaling in tumor progression. Our findings contribute to unraveling the molecular mechanisms underlying the divergent activities of IL-17 in cancer and provide rational targets for immunotherapies based on personalized approaches.

immunology↗

bioRxiv2020

PD-L1hi plasmablasts limit the T cell response during the acute phase of parasite infections

During infections with protozoan parasites or virus, T cell immunosuppression is generated simultaneously with a high B cell activation. Here, we show that in T. cruzi infection, all plasmablasts detected had higher surface expression of PD-L1, than other mononuclear cells. PD-L1hi plasmablasts were induced in vivo in an antigen-specific manner and required help from Bcl-6+CD4+T cells. PD-L1hi expression was not a characteristic of all antibody-secreting cells since plasma cells found during the chronic phase of infection express PD-L1 but at lower levels. PD-L1hi plasmablasts were also present in mice infected with Plasmodium or with lymphocytic choriomeningitis virus, but not in mice with autoimmune disorders or immunized with T cell-dependent antigens. PD-L1hi plasmablasts suppressed T cell response, via PD-L1, in vitro and in vivo. Thus, this study reveals that extrafollicular PD-L1hi plasmablasts, which precede the germinal center (CG) response, are a suppressive population in infections that may influence T cell response. Brief summaryPathogens develop different strategies to settle in the host. We identified a plasmablats population induced by pathogens in acute infections which suppress T cell response.

immunology↗

bioRxiv2019

CD8+ T cell immunity is compromised by anti-CD20 treatment and rescued by IL-17A

Treatment with anti-CD20, used in many diseases in which B cells play a pathogenic role, has been associated with susceptibility to intracellular infections. Here, we studied the effect of anti-CD20 injection on CD8+ T cell immunity using an experimental model of Trypanosoma cruzi infection, in which CD8+ T cells play a pivotal role. C57BL/6 mice were treated with anti-CD20 for B cell depletion prior to T. cruzi infection. Infected anti-CD20-treated mice exhibited a CD8+ T cell response with a conserved expansion phase followed by an early contraction, resulting in a strong reduction in total and parasite-specific CD8+ T cells at 20 days postinfection. Anti-CD20 injection decreased the number of effector and memory CD8+ T cells and reduced the frequency of proliferating and cytokine producing CD8+ T cells. Accordingly, infected anti-CD20-treated mice presented a lower cytotoxicity of T. cruzi peptide-pulsed target cells in vivo. All of these alterations in CD8+ T cell immunity were associated with increased tissue parasitism. Anti-CD20 injection also dampened an established CD8+ T cell response, indicating that B cells were involved in the maintenance rather than the induction of CD8+ T cell immunity. Anti-CD20 injection also resulted in a marked reduction in the frequency of IL-6- and IL-17A-producing cells, and only rIL-17A injection partially restored the CD8+ T cell response in infected anti-CD20-treated mice. Thus, anti-CD20 reduced CD8+ T cell immunity, and IL-17A is a candidate for rescuing deficient responses either directly or indirectly.\n\nImportanceMonoclonal antibody targeting the CD20 antigen on B cells is used to treat the majority of Non-Hodgkin lymphoma patients and some autoimmune disorders. This therapy generates adverse effects, notably opportunistic infections and activation of viruses from latency. Here, using the infection murine model with the intracellular parasite Trypanosoma cruzi, we report that anti-CD20 treatment not only affects B cell response but also CD8+ T cells, the most important immune effectors involved in control of intracellular pathogens. Anti-CD20 treatment, directly or indirectly, affects cytotoxic T cell number and function and this deficient response was rescued by the cytokine IL-17A. The identification of IL-17A as the cytokine capable of reversing the poor response of CD8+ T cells provide information about a potential therapeutic treatment aimed at enhancing defective immunity induced by B cell depletion.

immunology↗

bioRxiv2018

IL-17RA-signaling modulates CD8+ T cell survival and exhaustion during Trypanosoma cruzi infection

The IL-17 family contributes to host defense against many intracellular pathogens by mechanisms not fully understood. CD8+ T lymphocytes are key elements against intracellular microbes and their survival and appropriate response is orchestrated by several cytokines. Here, we demonstrated that IL-17RA-signaling cytokines sustain pathogen-specific CD8+ T cell immunity. Absence of IL-17RA and IL-17A/F during Trypanosoma cruzi infection resulted in increased tissue parasitism and reduced frequency of parasite-specific CD8+ T cells. Impaired IL-17RA-signaling in vivo increased apoptosis of parasite-specific CD8+ T cells while recombinant IL-17 in vitro down-regulated the pro-apoptotic protein BAD and promoted activated CD8+ T cell survival. Phenotypic, functional and trancriptomic profiling showed that T. cruzi-specific CD8+ T cells arising in IL-17RA-deficient mice presented features of cell dysfunction. PD-L1 blockade partially restored the magnitude of CD8+ T cell responses and parasite control in these mice. Adoptive transfer experiments established that IL-17RA-signaling is intrinsically required for the proper maintenance of functional effector CD8+ T cells. Altogether, our results identify IL-17RA and IL-17A as critical factors for sustaining CD8+ T cell immunity to T. cruzi.

immunology↗