scholarly journals IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells

2013 ◽  
Vol 210 (3) ◽  
pp. 491-502 ◽  
Author(s):  
Shlomo Z. Ben-Sasson ◽  
Alison Hogg ◽  
Jane Hu-Li ◽  
Paul Wingfield ◽  
Xi Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Interleukin 1 ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
In Vivo Models ◽  
Ifn Γ

Here, we show that interleukin-1 (IL-1) enhances antigen-driven CD8 T cell responses. When administered to recipients of OT-I T cell receptor transgenic CD8 T cells specific for an ovalbumin (OVA) peptide, IL-1 results in an increase in the numbers of wild-type but not IL1R1−/− OT-I cells, particularly in spleen, liver, and lung, upon immunization with OVA and lipopolysaccharide. IL-1 administration also results in an enhancement in the frequency of antigen-specific cells that are granzyme B+, have cytotoxic activity, and/ or produce interferon γ (IFN-γ). Cells primed in the presence of IL-1 display enhanced expression of granzyme B and increased capacity to produce IFN-γ when rechallenged 2 mo after priming. In three in vivo models, IL-1 enhances the protective value of weak immunogens. Thus, IL-1 has a marked enhancing effect on antigen-specific CD8 T cell expansion, differentiation, migration to the periphery, and memory.

R-DOTAP (Versamune): A novel enantiospecific cationic lipid nanoparticle that induces CD4 and CD8 cellular immune responses to whole protein and tumor-specific peptide antigens.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15211-e15211
Author(s):  
Lauren Virginia Wood ◽  
Siva K Gandhapudi ◽  
Karuna Sundarapandiyan ◽  
Frank K Bedu-Addo ◽  
Gregory Conn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cationic Lipid ◽  
Cd8 T Cell ◽  
Lipid Nanoparticles ◽  
Type I ◽  
T Cell Epitopes ◽  
Ifn Γ

e15211 Background: Immunotherapy approaches are limited in their ability to induce antigen-specific CD8+ T cells in vivo able to recognize and kill tumor cells. We developed a novel immunotherapy approach using enantiomerically pure, R-DOTAP cationic lipid nanoparticles and tumor-derived T cell antigens, and previously demonstrated that R-DOTAP formulations efficiently prime cytotoxic T cells through enhanced cross presentation and induction of type I interferons.[1] A phase I clinical trial of a R-DOTAP HPV16 peptide formulation confirmed induction of strong in vivo HPV-specific CD8+ cytolytic T-cells without associated systemic toxicities. In this study, we assessed R-DOTAP nanoparticle formulations containing whole protein (ovalbumin) or long multi-epitope peptides from the tumor antigen TARP (T-cell alternate reading frame protein): a 58-residue protein overexpressed in prostate and breast cancers, documented to be immunogenic in humans. Methods: R-DOTAP formulations were prepared containing ovalbumin (OVA) or TARP peptides. C57BL/6K mice were immunized with 10 μg/mouse of OVA plus R-DOTAP, CFA or sucrose on Days 0, 15 and 30. OVA-specific cellular and humoral responses following vaccination were assessed by measuring splenic CD4 and CD8 T cell IFN-γ production and circulating OVA-specific antibodies in serum. HLA-A2 transgenic mice (AAD mice) were vaccinated with long, multi-epitope TARP peptides delivered as an R-DOTAP admixture or with CFA or sucrose on Days 0 and 7. Antigen-specific T cell responses were measured by IFN-γ ELISpot assay. Results: OVA R-DOTAP formulations induced strong antigen-specific effector CD4 and CD8 immune and memory responses detected 7 and 30 days, respectively, following vaccination as well as OVA-specific antibody responses. In TARP peptide vaccinated mice, R-DOTAP formulations were able to present multiple CD8 T cell epitopes and stimulate responses that were superior to CFA. Conclusions: Our results suggest that R-DOTAP is a versatile immune activating therapy that can be formulated with long, multi-epitope tumor-derived peptides or whole proteins. R-DOTAP formulations induce quantitatively robust antigen-specific CD4 and CD8 T cells in vivo compared to well-established immune stimulants. Reference: 1.Gandhapudi SK, Ward M, Bush JP et al. Antigen Priming with Enantiospecific Cationic Lipid Nanoparticles Induces Potent Antitumor CTL Responses through Novel Induction of a Type I IFN Response. J Immunol 2019;202:3524-3536

scholarly journals n-3 Polyunsaturated Fatty Acids Impede the TCR Mobility and the TCR–pMHC Interaction of Anti-Viral CD8+ T Cells

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 639 ◽  
Author(s):  
Younghyun Lim ◽  
Seyoung Kim ◽  
Sehoon Kim ◽  
Dong-In Kim ◽  
Kyung Won Kang ◽  
...  
Keyword(s):  
Fatty Acids ◽  
T Cells ◽  
T Cell ◽  
Polyunsaturated Fatty Acids ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Omega 3 ◽  
In Vivo Models

The immune-suppressive effects of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) on T cells have been observed via multiple in vitro and in vivo models. However, the precise mechanism that causes these effects is still undefined. In this study, we investigated whether n-3 PUFAs regulated T cell receptor (TCR) and peptide-major histocompatibility complex (pMHC) interactions. The expansion of anti-viral CD8+ T cells that endogenously synthesize n-3 PUFAs (FAT-1) dramatically decreased upon lymphocytic choriomeningitis virus (LCMV) infection in vivo. This decrease was not caused by the considerable reduction of TCR expression or the impaired chemotactic activity of T cells. Interestingly, a highly inclined and laminated optical sheet (HILO) microscopic analysis revealed that the TCR motility was notably reduced on the surface of the FAT-1 CD8+ T cells compared to the wild type (WT) CD8+ T cells. Importantly, the adhesion strength of the FAT-1 CD8+ T cells to the peptide-MHC was significantly lower than that of the WT CD8+T cells. Consistent with this result, treatment with docosahexaenoic acid (DHA), one type of n-3 PUFA, significantly decreased CD8+ T cell adhesion to the pMHC. Collectively, our results reveal a novel mechanism through which n-3 PUFAs decrease TCR-pMHC interactions by modulating TCR mobility on CD8+ T cell surfaces.

Clonal Expansion of Graft-Versus-Host Reactive CD8+ T Cells Is Dissociated from Full Effector Differentiation Following Delayed DLI.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2170-2170
Author(s):  
Ronjon Chakraverty ◽  
Barry Flutter ◽  
Hyeon-Seok Eom ◽  
Farnaz Fallah-Arani ◽  
Guiling Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Cd8 T Cell ◽  
Host Environment ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Ifn Γ

Abstract Extrinsic factors within the host environment are crucial in determining recruitment of graft-versus-host (GVH)-reactive T cells to peripheral tissues and the capacity of these cells to induce graft-versus-host disease (GVHD). In this study, we have examined how the host environment influences graft-versus-leukemia (GVL) activity. Transfer of small numbers of allogeneic T cells to freshly irradiated (TBI allo) mice induces both GVL and GVHD, whereas transfer of much higher numbers of T cells to established (>8 weeks) mixed chimeras (MC) can induce GVL without GVHD. Using an EL4 tumor protection assay and low doses of B10.A splenocytes (3 × 10e6, a dose 1 log lower than normally transferred to MC to induce GVL), we observed that tumor-free survival of recipient mice was greater following transfer to TBI allo B6 recipients than in B6 + B10.A → B6 MC. To determine the mechanisms for this disparity, we used a BALB/c recipient/B6 donor strain combination, in which we could track the distribution of donor T cells within secondary lymphoid organs and bone marrow (BM) following transfer to TBI allo or MC recipients. Despite similar expansions within the spleen, there was a significant delay in the accumulation of polyclonal donor T cells (B6 CD45.1) and transgenic 2C GVH-reactive CD8+ T-cells (bearing TCR specific for recipient antigen) in the BM of MC compared to TBI allo mice. Moreover, in vivo cytotoxicity of host B cell targets occurred rapidly and was virtually complete in TBI allo recipients, but was absent in MC even at late time points. To evaluate the acquisition of effector functions in a clonal GVH-reactive CD8+ T cell population, we sorted 2C T cells at intervals following transfer and performed quantitative RT-PCR of molecules linked to effector differentiation. Strikingly, transcription of IFN-γ, granzyme B and TNF-α was significantly higher in cells derived from TBI allo hosts compared to MC. Similar differences in IFN-γ and granzyme B protein expression were confirmed in the polyclonal donor CD8+ T cell population. Since, full GVL activity might also depend upon the survival of GVH-reactive CTL, we also examined the viability of donor T cells during the initial response in both environments. We observed higher rates of sustained 2C CD8+ T cell apoptosis (as indicated by annexin V staining) following T cell transfer to MC. Furthermore, we also detected lower expression of common γ chain cytokine receptors that mediate responsiveness to IL-2, IL-7 and IL-15, upon donor T cells from MC. However, following secondary co-transfer to syngeneic recipients for 21 days, memory phenotype polyclonal donor CD8+ T cells derived from established MC (CD45.1+) were recovered to a greater extent than T cells initially derived from TBI allo mice (Thy1.1+), arguing against any intrinsic defect in the viability of GVH-reactive T cell populations emerging in the former setting. Indeed, when co-cultured in the presence of individual cytokines, MC-derived CD8+ T cells maintained viability to a greater (IL-2, IL-7) or equivalent (IL-15) extent as TBI allo-derived cells. Taken together, these data suggest that disparity in GVL activity following to TBI allo recipients and MC can be explained by differences in the effector function and survival of anti-host CTL in quiescent MC environment. Reduced GVL activity of donor T cells on a per-cell basis in MC can be compensated for by transferring greater numbers of cells.

scholarly journals T Cell–Independent Interleukin 15rα Signals Are Required for Bystander Proliferation

2001 ◽  
Vol 194 (8) ◽  
pp. 1187-1194 ◽  
Author(s):  
James P. Lodolce ◽  
Patrick R. Burkett ◽  
David L. Boone ◽  
Marcia Chien ◽  
Averil Ma
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Bone Marrow Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Poly I:C ◽  
T Cell Homeostasis ◽  
Memory Cd8 T Cells

Cytokine driven or “bystander” proliferation of T cells occurs in vivo independently of major histocompatibility complex–T cell receptor interactions. This process may be important for supporting T cell homeostasis and facilitating T cell responses to microbial antigens, and may involve the cytokine interleukin (IL)-15. In this study, we find that IL-15Rα–deficient (IL-15Rα−/−) mice fail to undergo poly I:C or IL-15 driven bystander proliferation of CD8+ T cells. Surprisingly, IL-15Rα−/− CD8+ T cells proliferate in response to poly I:C when adoptively transferred into normal mice, and normal CD8+ T cells fail to proliferate in IL-15Rα−/− mice. Normal mice reconstituted with IL-15Rα−/− bone marrow cells also fail to exhibit bystander responses. Thus, CD8+ T cell independent IL-15Rα signals from radiation sensitive hematopoietic cells are likely required for bystander responses. Moreover, normal CD8+ T cells proliferate in IL-15Rα−/− mice after treatment with IL-15. Therefore, IL-15Rα signals may mediate a positive feedback loop involving the further physiological production of IL-15. These findings provide new insights into how IL-15Rα supports memory phenotype CD8+ T cell proliferation, and suggest novel mechanisms by which memory CD8+ T cells are maintained in vivo.

scholarly journals Multi-Dimensional Analysis of Immune Signature Predicts Response to Decitabine Treatment in Elderly Patients with AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1526-1526
Author(s):  
Chenchen Zhao ◽  
Bei Jia ◽  
Liru Wang ◽  
David F. Claxton ◽  
W. Christopher Ehmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Outcome ◽  
Cd8 T Cells ◽  
Immune Status ◽  
Granzyme B ◽  
Cd8 T Cell ◽  
Immune Signature ◽  
Ifn Γ

Abstract Treatment for elderly AML patients who are unfit for intensive chemotherapy remains challenging. Induction with hypomethylating agents (HMA) are the most commonly used approach, however the rate of complete remission (CR) is only around 20% and median survival of 7-12 months. Clearly how to improve the clinical outcome in this patient population is an unmet need. Immunotherapy is promising in cancer treatment. A recent study demonstrated that HMA enhanced PD-1 pathway in MDS and AML patients (Yang et al., Leukemia 2014), suggesting a role of combining HMA and immunotherapy in leukemia therapeutics. To optimize this strategy, it is crucial to understand the interaction between HMA and immune response in AML. Here we performed both phenotypic and functional analysis on clinical samples collected from AML patients undergoing treatment of decitabine (DAC), a broadly used HMA. We aim to determine 1) how DAC influences the immune system; and 2) whether the immune status in AML patients predict the response to DAC treatment. Total of 22 peripheral blood samples from 11 AML patients receiving DAC were examined. Samples were collected at the time of prior to and 1-month post DAC treatment. We conducted a comprehensive phenotypic analysis of immune markers characterizing each immune component (T cells, B cells, NK, NKT, monocytes, myeloid-derived suppressor cells, and dendritic cells) and expression patterns of co-stimulatory or inhibitory molecules. In addition, perforin, granzyme B and cytokine release in response to anti-CD3/CD28 stimulation were examined to determine the functional status of T cells. A total of 45 markers separated in 8 overlapped staining panels were tested by flow cytometry. We first assessed the impact of DAC on the immune response in AML. Comparing the paired samples prior to vs. post treatment from the same patients, we observed an increase of the percentage of NK cells, as well as their expression of granzyme B and perforin upon DAC treatment. In contrast, DAC appears to cause CD8 T cell suppression as CD8 T cells from post-DAC samples showed higher PD-1 expression whereas lower IFN-γ production. We next investigated the predictive value of immune status for the response to DAC treatment. Among the 18 evaluable samples, we defined 10 responders (CR/Cri/PR) vs. 8 non-responders (treatment failure) based on the ELN 2017 recommendations. The correlation of immune characteristics to the clinical response was carefully examined. We started with an unsupervised principal component analysis (PCA), which revealed a distinguished pattern between the responders and non-responders (Fig. 1A). This encouraging observation suggests an association of immune signature to clinical outcome. Subsequent analysis demonstrated a major contribution of CD8 T cells to the association. We then focused on the phenotypic and functional analysis of CD8 T cells in responders vs. non-responders. We found a significantly higher percentage of terminal differentiated cells in non-responders compared with that of responders. Importantly, in the perspective of phenotypes, hierarchical clustering on markers of CD8 T cells divided samples into two major clades, 7 of 8 samples (87.5%) were responders on one branch and 7 of 10 samples (70%) were non-responders on the other. Most responders expressed lower frequency of inhibitory receptors and higher frequency of stimulatory receptors, whereas non-responders showed the opposite trend (Fig. 1B). The significant difference of these receptors was validated in paired t test analysis. Functional studies also showed more IFN-γ production in responders. Interestingly the intracellular staining of perforin and granzyme B was higher in non-responders, likely due to exhausted T cells that are unable to release these particles extracellularly. Collectively, our study discovered the vital role of the immune signature in predicting clinical outcome in AML. High functional CD8 T cell status, manifested by more capability of IFN-γ production, enhanced stimulatory molecule and low inhibitory receptor expression, associated with effective clinical response to DAC treatment. In addition, CD8 T cell function was down-regulated upon DAC treatment. Our results provide a strong rationale for integrating immunotherapy into HMA treatment in AML, also highlight the importance of immune signature analysis in the future trial design for this clinical setting. Disclosures No relevant conflicts of interest to declare.

scholarly journals Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

2016 ◽  
Vol 90 (24) ◽  
pp. 11259-11278 ◽  
Author(s):  
Anmol Chandele ◽  
Jaturong Sewatanon ◽  
Sivaram Gunisetty ◽  
Mohit Singla ◽  
Nattawat Onlamoon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dengue Virus ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Tcr Signaling ◽  
Hla Dr ◽  
Ifn Γ

ABSTRACT Epidemiological studies suggest that India has the largest number of dengue virus infection cases worldwide. However, there is minimal information about the immunological responses in these patients. CD8 T cells are important in dengue, because they have been implicated in both protection and immunopathology. Here, we provide a detailed analysis of HLA-DR + CD38 + and HLA-DR − CD38 + effector CD8 T cell subsets in dengue patients from India and Thailand. Both CD8 T cell subsets expanded and expressed markers indicative of antigen-driven proliferation, tissue homing, and cytotoxic effector functions, with the HLA-DR + CD38 + subset being the most striking in these effector qualities. The breadth of the dengue-specific CD8 T cell response was diverse, with NS3-specific cells being the most dominant. Interestingly, only a small fraction of these activated effector CD8 T cells produced gamma interferon (IFN-γ) when stimulated with dengue virus peptide pools. Transcriptomics revealed downregulation of key molecules involved in T cell receptor (TCR) signaling. Consistent with this, the majority of these CD8 T cells remained IFN-γ unresponsive even after TCR-dependent polyclonal stimulation (anti-CD3 plus anti-CD28) but produced IFN-γ by TCR-independent polyclonal stimulation (phorbol 12-myristate 13-acetate [PMA] plus ionomycin). Thus, the vast majority of these proliferating, highly differentiated effector CD8 T cells probably acquire TCR refractoriness at the time the patient is experiencing febrile illness that leads to IFN-γ unresponsiveness. Our studies open novel avenues for understanding the mechanisms that fine-tune the balance between CD8 T cell-mediated protective versus pathological effects in dengue. IMPORTANCE Dengue is becoming a global public health concern. Although CD8 T cells have been implicated both in protection and in the cytokine-mediated immunopathology of dengue, how the balance is maintained between these opposing functions remains unknown. We comprehensively characterized CD8 T cell subsets in dengue patients from India and Thailand and show that these cells expand massively and express phenotypes indicative of overwhelming antigenic stimulus and tissue homing/cytotoxic-effector functions but that a vast majority of them fail to produce IFN-γ in vitro . Interestingly, the cells were fully capable of producing the cytokine when stimulated in a T cell receptor (TCR)-independent manner but failed to do so in TCR-dependent stimulation. These results, together with transcriptomics, revealed that the vast majority of these CD8 T cells from dengue patients become cytokine unresponsive due to TCR signaling insufficiencies. These observations open novel avenues for understanding the mechanisms that fine-tune the balance between CD8-mediated protective versus pathological effects.

scholarly journals Tumor Rejection Induced by CD70-mediated Quantitative and Qualitative Effects on Effector CD8+ T Cell Formation

2004 ◽  
Vol 199 (11) ◽  
pp. 1595-1605 ◽  
Author(s):  
Ramon Arens ◽  
Koen Schepers ◽  
Martijn A. Nolte ◽  
Michiel F. van Oosterwijk ◽  
René A.W. van Lier ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Formation ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Tumor Rejection ◽  
Dependent Manner ◽  
Ifn Γ

In vivo priming of antigen-specific CD8+ T cells results in their expansion and differentiation into effector T cells followed by contraction into a memory T cell population that can be maintained for life. Recent evidence suggests that after initial antigenic stimulation, the magnitude and kinetics of the CD8+ T cell response are programmed. However, it is unclear to what extent CD8+ T cell instruction in vivo is modulated by costimulatory signals. Here, we demonstrate that constitutive ligation of the tumor necrosis factor receptor family member CD27 by its ligand CD70 quantitatively augments CD8+ T cell responses to influenza virus infection and EL-4 tumor challenge in vivo by incrementing initial expansion and maintaining higher numbers of antigen-specific T cells in the memory phase. Concomitantly, the quality of antigen-specific T cells improved as evidenced by increased interferon (IFN)-γ production and a greater cytotoxic potential on a per cell basis. As an apparent consequence, the superior effector T cell formation induced by CD70 protected against a lethal dose of poorly immunogenic EL4 tumor cells in a CD8+ T cell– and IFN-γ–dependent manner. Thus, CD70 costimulation enhances both the expansion and per cell activity of antigen-specific CD8+ T cells.

scholarly journals Swift Development of Protective Effector Functions in Naive Cd8+ T Cells against Malaria Liver Stages

2001 ◽  
Vol 194 (2) ◽  
pp. 173-180 ◽  
Author(s):  
Gen-ichiro Sano ◽  
Julius C.R. Hafalla ◽  
Alexandre Morrot ◽  
Ryo Abe ◽  
Juan J. Lafaille ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Cell Receptor ◽  
Plasmodium Yoelii ◽  
Parasite Development ◽  
Effector Functions ◽  
Ifn Γ

We generated T cell receptor transgenic mice specific for the liver stages of the rodent malaria parasite Plasmodium yoelii and studied the early events in the development of in vivo effector functions in antigen-specific CD8+ T cells. Differently to activated/memory cells, naive CD8+ T cells are not capable of exerting antiparasitic activity unless previously primed by parasite immunization. While naive cells need to differentiate before achieving effector status, the time required for this process is very short. Indeed, interferon (IFN)-γ and perforin mRNA are detectable 24 h after immunization and IFN-γ secretion and cytotoxic activity are detected ex vivo 24 and 48 h after immunization, respectively. In contrast, the proliferation of CD8+ T cells begins after 24 h and an increase in the total number of antigen-specific cells is detected only after 48 h. Remarkably, a strong CD8+ T cell–mediated inhibition of parasite development is observed in mice challenged with viable parasites only 24 h after immunization with attenuated parasites. These results indicate that differentiation of naive CD8+ T cells does not begin only after extensive cell division, rather this process precedes or occurs simultaneously with proliferation.

scholarly journals Virally Activated CD8 T Cells Home to Mycobacterium bovis BCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice

2006 ◽  
Vol 75 (3) ◽  
pp. 1154-1166 ◽  
Author(s):  
Laura H. Hogan ◽  
Dominic O. Co ◽  
Jozsef Karman ◽  
Erika Heninger ◽  
M. Suresh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Cd8 T Cells ◽  
Bacterial Load ◽  
Granulomatous Inflammation ◽  
Cd8 T Cell ◽  
Activated T Cells ◽  
Immunodeficient Mice ◽  
Ifn Γ

ABSTRACT The effect of secondary infections on CD4 T-cell-regulated chronic granulomatous inflammation is not well understood. Here, we have investigated the effect of an acute viral infection on the cellular composition and bacterial protection in Mycobacterium bovis strain bacille Calmette-Guérin (BCG)-induced granulomas using an immunocompetent and a partially immunodeficient murine model. Acute lymphocytic choriomeningitis virus (LCMV) coinfection of C57BL/6 mice led to substantial accumulation of gamma interferon (IFN-γ)-producing LCMV-specific T cells in liver granulomas and increased local IFN-γ. Despite traffic of activated T cells that resulted in a CD8 T-cell-dominated granuloma, the BCG liver organ load was unaltered from control levels. In OT-1 T-cell-receptor (TCR) transgenic mice, ovalbumin (OVA) immunization or LCMV coinfection of BCG-infected mice induced CD8 T-cell-dominated granulomas containing large numbers of non-BCG-specific activated T cells. The higher baseline BCG organ load in this CD8 TCR transgenic animal allowed us to demonstrate that OVA immunization and LCMV coinfection increased anti-BCG protection. The bacterial load remained substantially higher than in mice with a more complete TCR repertoire. Overall, the present study suggests that peripherally activated CD8 T cells can be recruited to chronic inflammatory sites, but their contribution to protective immunity is limited to conditions of underlying immunodeficiency.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

Sign in / Sign up

Export Citation Format

Share Document