Combining chemotherapy and programmed death 1 (PD-1) blockade to induce a T-cell response in patients with metastatic triple negative breast cancer (mTNBC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11563-11563 ◽  
Author(s):  
Elias Obeid ◽  
Chun Zhou ◽  
Alexander Macfarlane ◽  
R. Katherine Alpaugh ◽  
Cecilia McAleer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
T Cell Response ◽  
Number Of Patients ◽  
Correlative Studies ◽  
Immune Changes

11563 Background: Correlative studies to determine the effect of combining chemotherapy (CT) simultaneously with checkpoint inhibition on the peripheral immune response are planned as part of a clinical trial in MTNB. The trial design is a Safety run-in, into a randomized phase II trial of combination pembrolizumab (P) with carboplatin (C) and gemcitabine (G) in patients with mTNBC. One key concern is that CT may suppress immune cell function, thereby diminishing the efficacy of PD-1 blockade. Methods: Patients with a diagnosis of mTNBC are recruited to this trial with a Safety Run-in (N = 6-12 subjects), followed by a randomized design of C + G with/without P (2:1 randomization, N = 75). Safety run-in consists of P 200 mg on day 1 of each 21-day cycle, and C (AUC2) + G (800mg/m2) on days 1 and 8. Patients are consented for a peripheral blood (PB) collection pre-cycle 1 and on day 1 of cycle 3, in order to phenotype immune system changes by flow-cytometry. Results: Six patients have been recruited as of this interim analysis. Data from PB analysis of 3 on-treatment patients is available. In 2 subjects, the activation marker CD69 increased on CD4+ and CD8+ T cells from baseline, indicating enhanced T cell function. Also the ratio of CD8+ T cells to regulatory T cells (CD25high CD127low) has increased. Both patients expressed PD-1 on T cells at baseline. The 2 subjects with evidence for enhanced immune response have a continued clinical benefit (12 cycles subject 1, 8 cycles subject 2). In contrast, subject 3 (who discontinued P and received corticosteroids for grade a 2 immune-related hepatitis during cycle 2) lacked expression of PD-1 on T cells and did not exhibit these immune changes, and her disease clinically progressed after 4 cycles of CT. Conclusions: Although comprising a very limited number of patients, early analysis from our correlative studies of combining CT with the PD-1 blockade revealed evidence for effective immune stimulation in two subjects. Furthermore, immune changes accompanied a lasting clinical response. Although early, we conclude that combining CT with checkpoint blockade can achieve its goal of unleashing an anti-tumor immune response in mTNBC patients. Clinical trial information: NCT02755272.

scholarly journals Divergent Impact of Glucose Availability on Human Virus-Specific and Generically Activated CD8 T Cells

Metabolites ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 461
Author(s):  
Jenifer Sanchez ◽  
Ian Jackson ◽  
Katie R. Flaherty ◽  
Tamara Muliaditan ◽  
Anna Schurich
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Cell Immune Response ◽  
Complex Nature ◽  
Human Virus ◽  
Glucose Availability

Upon activation T cells engage glucose metabolism to fuel the costly effector functions needed for a robust immune response. Consequently, the availability of glucose can impact on T cell function. The glucose concentrations used in conventional culture media and common metabolic assays are often artificially high, representing hyperglycaemic levels rarely present in vivo. We show here that reducing glucose concentration to physiological levels in culture differentially impacted on virus-specific compared to generically activated human CD8 T cell responses. In virus-specific T cells, limiting glucose availability significantly reduced the frequency of effector-cytokine producing T cells, but promoted the upregulation of CD69 and CD103 associated with an increased capacity for tissue retention. In contrast the functionality of generically activated T cells was largely unaffected and these showed reduced differentiation towards a residency phenotype. Furthermore, T cells being cultured at physiological glucose concentrations were more susceptible to viral infection. This setting resulted in significantly improved lentiviral transduction rates of primary cells. Our data suggest that CD8 T cells are exquisitely adapted to their niche and provide a reminder of the need to better mimic physiological conditions to study the complex nature of the human CD8 T cell immune response.

scholarly journals Direct Visualization of Antigen-specific CD8+T Cells during the Primary Immune Response to Epstein-Barr Virus In Vivo

1998 ◽  
Vol 187 (9) ◽  
pp. 1395-1402 ◽  
Author(s):  
M.F.C. Callan ◽  
L. Tan ◽  
N. Annels ◽  
G.S. Ogg ◽  
J.D.K. Wilson ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Epstein Barr Virus ◽  
T Cell Response ◽  
Primary Immune Response ◽  
Barr Virus ◽  
Epstein Barr

Primary infection with virus can stimulate a vigorous cytotoxic T cell response. The magnitude of the antigen-specific component versus the bystander component of a primary T cell response remains controversial. In this study, we have used tetrameric major histocompatibility complex–peptide complexes to directly visualize antigen-specific cluster of differentration (CD)8+ T cells during the primary immune response to Epstein-Barr virus (EBV) infection in humans. We show that massive expansion of activated, antigen-specific T cells occurs during the primary response to this virus. In one individual, T cells specific for a single EBV epitope comprised 44% of the total CD8+ T cells within peripheral blood. The majority of the antigen-specific cells had an activated/memory phenotype, with expression of human histocompatibility leukocyte antigen (HLA) DR, CD38, and CD45RO, downregulation of CD62 leukocyte (CD62L), and low levels of expression of CD45RA. After recovery from AIM, the frequency of antigen-specific T cells fell in most donors studied, although populations of antigen-specific cells continued to be easily detectable for at least 3 yr.

scholarly journals A gammaherpesvirus-secreted activator of Vβ4+ CD8+ T cells regulates chronic infection and immunopathology

2008 ◽  
Vol 205 (3) ◽  
pp. 669-684 ◽  
Author(s):  
Andrew G. Evans ◽  
Janice M. Moser ◽  
Laurie T. Krug ◽  
Veranika Pozharskaya ◽  
Ana L. Mora ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Murine Gammaherpesvirus

Little is known about herpesvirus modulation of T cell activation in latently infected individuals or the implications of such for chronic immune disorders. Murine gammaherpesvirus 68 (MHV68) elicits persistent activation of CD8+ T cells bearing a Vβ4+ T cell receptor (TCR) by a completely unknown mechanism. We show that a novel MHV68 protein encoded by the M1 gene is responsible for Vβ4+ CD8+ T cell stimulation in a manner reminiscent of a viral superantigen. During infection, M1 expression induces a Vβ4+ effector T cell response that resists functional exhaustion and appears to suppress virus reactivation from peritoneal cells by means of long-term interferon-γ (IFNγ) production. Mice lacking an IFNγ receptor (IFNγR−/−) fail to control MHV68 replication, and Vβ4+ and CD8+ T cell activation by M1 instead contributes to severe inflammation and multiorgan fibrotic disease. Thus, M1 manipulates the host CD8+ T cell response in a manner that facilitates latent infection in an immunocompetent setting, but promotes disease during a dysregulated immune response. Identification of a viral pathogenecity determinant with superantigen-like activity for CD8+ T cells broadens the known repertoire of viral immunomodulatory molecules, and its function illustrates the delicate balance achieved between persistent viruses and the host immune response.

scholarly journals Obligatory Requirement for Antibody in Recovery from a Primary Poxvirus Infection

2006 ◽  
Vol 80 (13) ◽  
pp. 6339-6344 ◽  
Author(s):  
Geeta Chaudhri ◽  
Vijay Panchanathan ◽  
Horst Bluethmann ◽  
Gunasegaran Karupiah
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Ectromelia Virus ◽  
B Cell Function

ABSTRACT To understand the correlates of protective immunity against primary variola virus infection in humans, we have used the well-characterized mousepox model. This is an excellent surrogate small-animal model for smallpox in which the disease is caused by infection with the closely related orthopoxvirus, ectromelia virus. Similarities between the two infections include virus replication and transmission, aspects of pathology, and development of pock lesions. Previous studies using ectromelia virus have established critical roles for cytokines and effector functions of CD8 T cells in the control of acute stages of poxvirus infection. Here, we have used mice deficient in B cells to demonstrate that B-cell function is also obligatory for complete virus clearance and recovery of the host. In the absence of B cells, virus persists and the host succumbs to infection, despite the generation of CD8 T-cell responses. Intriguingly, transfer of naive B cells or ectromelia virus-immune serum to B-cell-deficient mice with established infection allowed these animals to clear virus and fully recover. In contrast, transfer of ectromelia virus-immune CD8 T cells was ineffective. Our data show that mice deficient in CD8 T-cell function die early in infection, whereas those deficient in B cells or antibody production die much later, indicating that B-cell function becomes critical after the effector phase of the CD8 T-cell response to infection subsides. Strikingly, our results show that antibody prevents virus from seeding the skin and forming pock lesions, which are important for virus transmission between hosts.

scholarly journals Regulation of T Cells in Cancer by Nitric Oxide

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2655
Author(s):  
Inesa Navasardyan ◽  
Benjamin Bonavida
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Target Cells ◽  
Effector Cells ◽  
Cell Functions

The T cell-mediated immune response is primarily involved in the fight against infectious diseases and cancer and its underlying mechanisms are complex. The anti-tumor T cell response is regulated by various T cell subsets and other cells and tissues in the tumor microenvironment (TME). Various mechanisms are involved in the regulation of these various effector cells. One mechanism is the iNOS/.NO that has been reported to be intimately involved in the regulation and differentiation of the various cells that regulate the anti-tumor CD8 T cells. Both endogenous and exogenous .NO are implicated in this regulation. Importantly, the exposure of T cells to .NO had different effects on the immune response, depending on the .NO concentration and time of exposure. For instance, iNOS in T cells regulates activation-induced cell death and inhibits Treg induction. Effector CD8 T cells exposed to .NO result in the upregulation of death receptors and enhance their anti-tumor cytotoxic activity. .NO-Tregs suppress CD4 Th17 cells and their differentiation. Myeloid-derived suppressor cells (MDSCs) expressing iNOS inhibit T cell functions via .NO and inhibit anti-tumor CD8 T cells. Therefore, both .NO donors and .NO inhibitors are potential therapeutics tailored to specific target cells that regulate the T cell effector anti-tumor response.

scholarly journals Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

2015 ◽  
Vol 112 (10) ◽  
pp. 3050-3055 ◽  
Author(s):  
Rama S. Akondy ◽  
Philip L. F. Johnson ◽  
Helder I. Nakaya ◽  
Srilatha Edupuganti ◽  
Mark J. Mulligan ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Yellow Fever ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Virus Load

CD8 T cells are a potent tool for eliminating intracellular pathogens and tumor cells. Thus, eliciting robust CD8 T-cell immunity is the basis for many vaccines under development. However, the relationship between antigen load and the magnitude of the CD8 T-cell response is not well-described in a human immune response. Here we address this issue by quantifying viral load and the CD8 T-cell response in a cohort of 80 individuals immunized with the live attenuated yellow fever vaccine (YFV-17D) by sampling peripheral blood at days 0, 1, 2, 3, 5, 7, 9, 11, 14, 30, and 90. When the virus load was below a threshold (peak virus load < 225 genomes per mL, or integrated virus load < 400 genome days per mL), the magnitude of the CD8 T-cell response correlated strongly with the virus load (R2∼ 0.63). As the virus load increased above this threshold, the magnitude of the CD8 T-cell responses saturated. Recent advances in CD8 T-cell–based vaccines have focused on replication-incompetent or single-cycle vectors. However, these approaches deliver relatively limited amounts of antigen after immunization. Our results highlight the requirement that T-cell–based vaccines should deliver sufficient antigen during the initial period of the immune response to elicit a large number of CD8 T cells that may be needed for protection.

Heterogeneity within Antigen-Specific T Cell Responses Revealed by Differential Dynamics of TCR Downregulation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3851-3851
Author(s):  
Holbrook E. Kohrt ◽  
Chen-Tsen Shu ◽  
Susan P. Holmes ◽  
Jeffrey Weber ◽  
Peter P. Lee
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Functional Status ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Marrow Transplant ◽  
Specific Patient ◽  
Chromium Release

Abstract Cytomegalovirus (CMV) is a known cause of significant morbidity, including CMV pneumonitis, among bone marrow transplant patients. Studies investigating the immune response to CMV pneumonitis within bronchoalveolar lavage samples illustrate a predominance of CD8 T cells. However, CD8 T cell infiltration does not correlate with clinical response. Likewise, cancer vaccine trials have failed to show a correlation between induction of antigen-specific CD8 T cell populations and clinical tumor response. Based on the recent finding that T cells downregulate the T cell receptor (TCR) upon activation, we demonstrate by stimulating antigen-specific T cells with graded amounts of cognate peptides that individual cells lose tetramer reactivity with different dynamics which reflects previously uncharacterized heterogeneity within the population. We analyzed response among virus-, CMV PP65 and EBV BMLF1, and tumor associated antigen- (TAA), MART and gp100, specific CD8 T cell clones and patient samples. Critical T cell response characteristics including sensitivity to antigen, recognition efficiency (RE, also referred to as functional avidity), and relative functional state were calculated based on TCR downregulation. We show TCR downregulation represents an accurate assessment of average T cell function with direct correlation to killing capacity by chromium release (r2 of.907, P<0.01) and degranulation by CD107 mobilization (r2 of.99, P=0.016). However, despite correlation of average T cell function, we found heterogeneity in T cell sensitivity and relative functional status not evident by chromium release or CD107 mobilization alone. TCR downregulation among viral clones with homogeneous tetramer+ populations appeared similar, however one CMV-specific clone was unique in lower RE (7.18, group mean 7.32) and poor functional status (29.6% of tetramer+ CD8 T cells failed to downregulate at supraphysiologic concentrations of stimulating peptide, group mean 9.1%) despite the highest sensitivity (11.6, group mean 8.9). Among CMV-specific patient samples, size of tetramer+ population was not correlated with CD8 T cell sensitivity or RE. Patient 10539 with the largest tetramer+ population (1.8%, group range 0.5–1.8%), demonstrated the lowest sensitivity (10.2, group range 10.2–12.3) and only average RE (9.2, group range 7.8–10.2). TAA-specific CD8 T cell clones and patient samples post-vaccination with heteroclitic peptide contained significant heterogeneity in response to native and heteroclitic peptides. Despite equivalent percent tetramer+ populations, gp100-specific patient samples were significantly less sensitive (8.9 vs 10.8) with lower RE (7.3 vs 9.2) and greater percent relatively nonfunctional (38% vs 2%) to native versus heteroclitic peptide. These findings suggest failure of CD8 T cells specific for CMV or tumor antigens to produce a clinically significant response may be due to heterogeneity in the T cell population. Specifically, in states of low antigen expression, such as chronic viral infection and cancer, CD8 T cells of high sensitivity and RE with adequate functional status may be required for competent in vivo immune response. It is thus important to understand and appreciate the heterogeneity which may exist within antigen-specific T cell populations, and its clinical implications, to better predict efficacy of the immune response to cancer vaccination or following bone marrow transplant.

Cytomegalovirus Specific Immunity Protects From Cytomegalovirus Replication After Hematopoietic Stem Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1281-1281
Author(s):  
Fátima de la Cruz Vicente ◽  
Omar BenMarzouk-Hidalgo ◽  
Irene Gracia-Ahufinger ◽  
Raul García-Lozano ◽  
Manuela Aguilar-Guisado ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Immune Reconstitution ◽  
T Cell Response ◽  
Cmv Infection ◽  
Post Transplant

Abstract Abstract 1281 Background: Cytomegalovirus (CMV) end-organ disease is a serious complication after allogeneic stem cell transplantation (Allo-SCT). The quality of the post-transplant immune reconstitution plays a crucial role in the development of both, post-transplant infections and relapse of the underlying disease, two of the main factors conditioning post-transplant mortality and hence final survival. The relationship between viral replication and CMV specific immune reconstitution has not been completely unveiled. This knowledge would allow identifying patients at risk for developing CMV disease and eventually improving their clinical management. Objectives: to analyze the relationship between CMV replication and specific CMV immune reconstitution and the potential influence of this relationship in main clinical outcomes. Patients and Methods: A prospective study of consecutive recipients of Allo-SCT was performed from June 2008 through December 2009 at a single institution. Blood samples were collected from one week before transplant, weekly during the first three months after transplant, every other week from month three to six and monthly from month seven to complete one year of follow up. CMV viral load was determined by real time PCR and CMV-specific T cell response was determined by flow cytometry with surface markers and intracellular cytokine staining. The percentage of activated CD4+, CD8+ and CD3+ T cells expressing CD69 were considered positive when IFN-’Y cytokine secretion was over 0.25%. Chimerism of the isolated CD8+ T cell subpopulation was determined by PCR. CD69 expression and cytokine secretion were compared in both CD4+ and CD8+ T cells between the different time points and both subsets of patients by the Wilcoxon test. CMV viral load reduction without treatment administration was compared by Wilcoxon test. Differences were considered statistically significant for p-values < 0.05. All statistical analyses were performed using SPSS 16.0 software (Chicago, IL). Results: Twenty-six patients were enrolled in the study with a median age of 33 years (range:15-61). We identified two groups of patients. A first group of 18 (69.2%) patients developed CMV infection and acquired CMV-specific T cell response by median week 8 (range:1-22; Figure 1A). The decline in the incidence of CMV replication episodes correlated with the acquisition of CMV-specific T cell response (Linear regresion r2=0.781, Pearson correlation p=0.01). A second group of 8 patients (30.8%) never developed CMV infection after the transplant, with a median value of 2 weeks (range:1-7; Figure 1B). The time of the acquisition of CMV-specific T cell response for the group with viremia and for the non-viremic group (week 2 vs. week 8) was statistically different (p= 0.01). Fifteen per cent of the patients (n=4) developed end-organ disease. Three out of five patients with end-organ disease developed replication CMV episodes over 10,000 copies/ml, while only 1 out of 13 patients with no end-organ disease developed viral loads under 10,000 copies/ml (p=0.04). The percentage of positive CD8+ T cells expressing IFN-γ in the patients that developed disease tended to be lower than in the patients that did not develop disease (median percentage of IFN-g positive CD8 T cells 0.3 vs. 0.5, respectively). The chimerism of the CD8+ T cells subpopulation after acquiring the specific immune response was of complete donor origin for all the patients. Conclusions: Developing donor-derived T-cell mediated CMV-specific immune response within the following two weeks after the transplant is inversely associated with the development CMV infection. The level of CMV viral load may predict end-organ disease. The use of a tool to determine T-cell mediated CMV-specific immune response in the clinical practice may help to improve the management of these patients, avoiding unnecessary treatments, and predicting clinical outcomes. Disclosures: No relevant conflicts of interest to declare.

Dynamic Changes in Ex Vivo T-Cell Function After Viral Clearance in Chronic HCV Infection

2019 ◽  
Vol 220 (8) ◽  
pp. 1290-1301 ◽  
Author(s):  
Ji Won Han ◽  
Pil Soo Sung ◽  
Kyung Hwan Kim ◽  
Seon-Hui Hong ◽  
Eui-Cheol Shin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Ex Vivo ◽  
T Cell Response ◽  
Viral Clearance ◽  
Hcv Infection ◽  
T Cell Function ◽  
Chronic Hcv

Abstract Background Direct-acting antiviral (DAA) agents can successfully treat chronic hepatitis C virus (HCV) infection. However, the ex vivo HCV-specific T-cell function following viral clearance remains unknown. Methods We investigated functional alterations and phenotypic changes in ex vivo HCV-specific CD8+ T cells with a longitudinal analysis of 41 patients with chronic HCV infection who were undergoing DAA treatment. Results A patient subset exhibited a significantly increased T-cell response (mainly CD8+ T cells) at week 4 of treatment. However, this increased T-cell response diminished in later weeks. Relative to pretreatment levels, the ex vivo HCV-specific CD8+ T-cell frequency decreased at 12 weeks after the end of treatment, along with a decreased antigen-experienced CD8+ T-cell population. DAA treatment increased the proliferative capacity of HCV-specific CD8+ T cells, but this change was not correlated with ex vivo function. Patients experiencing viral breakthrough or relapse exhibited defective restoration of T-cell function. Conclusion Our present results indicated that DAA-mediated viral clearance only transiently restored ex vivo T-cell function, suggesting a need to enhance T-cell function in DAA-treated patients.

scholarly journals Pathogen-encoded evasion of CXCL10 and T cell responses

2019 ◽  
Author(s):  
Alejandro L. Antonia ◽  
Monica I. Alvarez ◽  
Esme Trahair ◽  
Kyle D. Gibbs ◽  
Kelly J. Pittman ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Chlamydia Trachomatis ◽  
Cd8 T Cells ◽  
Salmonella Enterica ◽  
T Cell Response ◽  
Host Immune System ◽  
Intracellular Pathogens ◽  
Lesion Development

AbstractClearance of intracellular pathogens, such asLeishmania (L.) major, depends on a well-regulated adaptive T cell response. Here we describe a pathogen-encoded mechanism to alter T cell recruitment by suppressing CXCL10, a chemokine that recruits CD4+ and CD8+ T cells by signaling through the CXCR3 receptor.L. majorsuppresses CXCL10 through the virulence factor and protease, glycoprotein-63(gp63).GP63 cleaves CXCL10 after amino acid A81, impairing T-cell chemotaxisin vitro.GP63 from either extracellular promastigotes or intracellular amastigotes is capable of cleaving CXCL10. Consistent with CXCL10 cleavage during infection, we observed GP63-mediated impairment of activated CD8+ T-cells in the draining lymph nodes of C57BL/6JWTmice. Correspondingly, in C57BL/6JWTmice,gp63deletion resulted in slower lesion development and a smaller maximum lesion size. However, infection in C57BL/6Jcxcr3−/−mice revealed the delay to lesion development required CXCR3 signaling. Finally,Salmonella entericaandChlamydia trachomatisinfection also suppress CXCL10, demonstrating convergent evolution of this immune evasion strategy in diverse intracellular pathogens. Understanding mechanisms of CXCL10 evasion may facilitate the development of novel therapeutic strategies to treat intracellular pathogens.Author SummaryLeishmaniasis is an infectious disease that affects over one million people annually. It is caused by intracellular parasites that have evolved to evade the host’s attempts to eliminate the parasite. The most common form of disease, cutaneous leishmaniasis, causes disfiguring skin lesions if the host immune system does not appropriately respond to the infection. A family of molecules called chemokines are critical for the recruitment of specific subsets of immune cells required to eliminate infection. Here, we demonstrate a novel mechanism that the parasiteLeishmania (L.) majoremploys to disrupt the immune response by interfering with chemokine signaling. By this strategy,L. majoruses a protease to cleave chemokines known to recruit T-cells required for fighting off infection. We show thatL. majorcleavage of these immune signals changes the recruitment of CD8+ T-cells and alters disease progression in mice. Finally, we observe that multiple common human intracellular pathogens, includingChlamydia trachomatisandSalmonella enterica, interfere with the same chemokines, suggesting a strong selective pressure to avoid this component of the immune response. Our study provides new insights into how intracellular pathogens interact with the host immune response to enhance pathogen survival and exacerbate disease outcomes.

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