scholarly journals Lactoferrin-Functionalized Noble Metal Nanoparticles as New Antivirals for HSV-2 Infection

2022 ◽  
Vol 10 (1) ◽  
pp. 110
Author(s):  
Malgorzata Krzyzowska ◽  
Marcin Chodkowski ◽  
Martyna Janicka ◽  
Dominika Dmowska ◽  
Emilia Tomaszewska ◽  
...  
Keyword(s):  
Immune Responses ◽  
Potent Inhibitor ◽  
Human Keratinocytes ◽  
Treated Group ◽  
Noble Metal Nanoparticles ◽  
Cytotoxic Activities ◽  
Mucosal Tissues ◽  
Ifn Γ ◽  
Better Than

(1) Background: Lactoferrin has been recognized as a potent inhibitor of human herpetic viruses, such as herpes simplex type 1 (HSV-1) and 2 (HSV-2). In this work, we tested if silver and gold nanoparticles modified with lactoferrin (LF-Ag/AuNPs) can become novel microbicides with additional adjuvant properties to treat genital herpes infection. (2) Methods: The antiviral and cytotoxic activities of LF-Ag/AuNPs were tested in human skin HaCaT and vaginal VK-2-E6/E7 keratinocytes. Viral titers and immune responses after treatment with LF-Ag/AuNPs were tested in murine vaginal HSV-2 infection. (3) Results: LF-Ag/AuNPs inhibited attachment and entry of HSV-2 in human keratinocytes much better than lactoferrin. Furthermore, pretreatment with LF-AgNPs led to protection from infection. Infected mice treated intravaginally with LF-Ag/AuNPs showed lower virus titers in the vaginal tissues and spinal cords in comparison to treatment with lactoferrin. Following treatment, vaginal tissues showed a significant increase in CD8+/granzyme B + T cells, NK cells and dendritic cells in comparison to NaCl-treated group. LF-Ag/AuNPs-treated animals also showed significantly better expression of IFN-γ, CXCL9, CXCL10, and IL-1β in the vaginal tissues. (4) Conclusions: Our findings show that LF-Ag/AuNPs could become effective novel antiviral microbicides with immune-stimulant properties to be applied upon the mucosal tissues.

scholarly journals Mycobacterium-Induced Potentiation of Type 1 Immune Responses and Protection against Malaria Are Host Specific

2005 ◽  
Vol 73 (12) ◽  
pp. 8369-8380 ◽  
Author(s):  
Kathleen R. Page ◽  
Anne E. Jedlicka ◽  
Benjamin Fakheri ◽  
Gregory S. Noland ◽  
Anup K. Kesavan ◽  
...  
Keyword(s):  
Immune Responses ◽  
Plasmodium Yoelii ◽  
Short Term ◽  
Necrosis Factor Alpha ◽  
The World ◽  
Peak Parasitemia ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Malaria and tuberculosis are endemic in many regions of the world, and coinfection with the two pathogens is common. In this study, we examined the effects of long- and short-term infection with Mycobacterium tuberculosis on the course of a lethal form of murine malaria in resistant (C57BL/6) and susceptible (BALB/c) mice. C57BL/6 mice coinfected with M. tuberculosis CDC1551 and Plasmodium yoelii 17XL had a lower peak parasitemia and increased survival compared to mice infected with P. yoelii 17XL alone. Splenic microarray analysis demonstrated potentiation of type 1 immune responses in coinfected C57BL/6 mice, which was especially prominent 5 days after infection with P. yoelii 17XL. Splenocytes from coinfected C57BL/6 mice produced higher levels of gamma interferon (IFN-γ) and tumor necrosis factor alpha than splenocytes from mice infected with either pathogen alone. Interestingly, mycobacterium-induced protection against lethal P. yoelii is mouse strain specific. BALB/c mice were significantly more susceptible than C57BL/6 mice to infection with P. yoelii 17XL and were not protected against lethal malaria by coinfection with M. tuberculosis. In addition, M. tuberculosis did not augment IFN-γ responses in BALB/c mice subsequently infected with P. yoelii 17XL. These data indicate that M. tuberculosis-induced potentiation of type 1 immune responses is associated with protection against lethal murine malaria.

Phagocytosis May Be a Regulatory Mechanism for Myeloid Dendritic Cells to Terminate Type 1 CD8+ T Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1654-1654
Author(s):  
Young-June Kim ◽  
Hal E. Broxmeyer
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Phagocytic Activity ◽  
Regulatory Mechanism ◽  
Gm Csf ◽  
T Cell Immune Responses ◽  
Ifn Γ

Abstract Abstract 1654 Poster Board I-680 CD8+ cytotoxic T cells are often ‘exhausted’ by programmed death-1 (PD-1) signaling, and subsequently the functions of these cells are terminated especially in a tumor environment or upon chronic HIV or HCV infection. Subsets of myeloid cells referred to as myeloid derived suppressor cells (MDSC) or regulatory dendritic cells (DCs) have been implicated in inducing exhaustion or termination of effector CD8+ T cells. To this end, we developed various myeloid-derived dendritic cell (DC) types in vitro from human CD14+ monocytes using M-CSF or GM-CSF in the presence of IL-4 with/without other cytokines, and characterized these DCs with respect to their capacity to induce PD-1 expression on and exhaustion of CD8+ T cells. We then assessed their impact on longevity of CD8+ T cells following coculture. Myeloid DCs developed in vitro with M-CSF and IL-4 for 5 days (referred to as M-DC) did not express ligand for PD-1 (PD-L1) nor did they induce PD-1 on CD8+ T cells. Thus, using M-DCs as starting cells, we sought determinant factors that could modulate M-DCs to express PD-L1 and thereby induce exhaustion of CD8+ T cells. In order to better monitor exhaustion processes, we incubated human peripheral CD8+ T cells for 5 days in the presence of IL-15, an important cytokine for maintaining viability, before coculture. M-DCs showed little impact on exhaustion or longevity of the CD8+ T cells. IL-10 converted M-DC into a distinct myeloid DC subset (referred to as M-DC/IL-10) with an ability to express PD-L1 as well as to induce PD-1 on cocultured CD8+ T cells. M-DC/IL-10 cells markedly suppressed proliferation of cocultured CD8+ T cells. M-DC/IL-10 cells were morphologically unique with many granules and filamentous structures around the cell periphery. These IL-10 effects on M-DC were completely abrogated in the presence of TNF-á. M-DC/IL-10 cells could be further differentiated into another myeloid DC subset in the presence of IFN-γ (referred to as M-DC/IL-10/IFN-γ) with an ability to express even higher levels of PD-L1 compared to M-DC/IL-10 cells. The most remarkable effect of M-DC/IL-10/IFN-γ cells on cocultured CD8+ T cells was a dramatic loss of CD8+ T cells. Light and confocal microscopic observations indicated that loss of CD8+ T cells was due to phagocytosis by M-DC/IL-10/IFN-γ cells. As IFN-γ, a type 1 cytokine which is induced in CD8+ T cells by IL-12 is essential for phagocytosis, we tested whether IL-12 treatment of CD8+ T cells could further enhance phagocytosis induced by M-DC/IL-10/IFN-γ cells. Indeed, IL-12 treatment greatly increased numbers of phagocytosed CD8+ T cells. In contrast, IL-4 treated CD8+ T cells became resistant to phagocytosis, suggesting IFN-γ producing (type1) CD8+ T cells may be primary target cells for the M-DC/IL-10 cells mediated phagocytosis. CD4+ T cells were not as susceptible as CD8+ T cells to phagocytosis. We failed to detect such phagocytic activity induced by prototype DCs generated with GM-CSF and IL-4. Phagocytic activity was not inhibited by various arginase-1 inhibitors suggesting that nitric oxide signaling may not mediate phagocytic activity. Neutralizing antibody to PD-L1 slightly but significantly lowered phagocytic activity suggesting that PD-L1/PD-1 interaction may be partially involved in this process. Myeloid DCs are thought to be immunogenic, actively inducing T cell immune responses. Our results demonstrate that myeloid DCs may play suppressive roles as well through induction of phagocytic activity, especially against IFN-γ producing CD8+ T cells. This may serve as a regulatory mechanism for type 1 CD8+ T cell immune responses in an IL-10 enriched microenvironment. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Innate Immune Responses of Colonic Epithelial Cells to Trichuris muris Are Similar in Mouse Strains That Develop a Type 1 or Type 2 Adaptive Immune Response

2006 ◽  
Vol 74 (11) ◽  
pp. 6280-6286 ◽  
Author(s):  
Matthew L. deSchoolmeester ◽  
Harinder Manku ◽  
Kathryn J. Else
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Subsequent Development ◽  
Trichuris Muris ◽  
Adaptive Immune ◽  
Ifn Γ

ABSTRACT Trichuris muris resides in intimate contact with its host, burrowing within cecal epithelial cells. However, whether the enterocyte itself responds innately to T. muris is unknown. This study investigated for the first time whether colonic intestinal epithelial cells (IEC) produce cytokines or chemokines following T. muris infection and whether divergence of the innate response could explain differentially polarized adaptive immune responses in resistant and susceptible mice. Increased expression of mRNA for the proinflammatory cytokines gamma interferon (IFN-γ) and tumor necrosis factor and the chemokine CCL2 (MCP-1) were seen after infection of susceptible and resistant strains, with the only difference in expression being a delayed increase in CCL2 in BALB/c IEC. These increases were ablated in MyD88−/− mice, and NF-κB p65 was phosphorylated in response to T. muris excretory/secretory products in the epithelial cell line CMT-93, suggesting involvement of the MyD88-NF-κB signaling pathway in IEC cytokine expression. These data reveal that IEC respond innately to T. muris. However, the minor differences identified between resistant and susceptible mice are unlikely to underlie the subsequent development of a susceptible type 1 (IFN-γ-dominated) or resistant type 2 (interleukin-4 [IL-4]/IL-13-dominated) adaptive immune response.

scholarly journals Curcumin Ameliorate Diabetes type 1 Complications through Decreasing Pro-inflammatory Cytokines in C57BL/6 Mice

2020 ◽  
Author(s):  
Yaser Jafari Khataylou ◽  
Somayeh Ahmadiafshar ◽  
Reza Rezaei ◽  
Saeid Parsamanesh ◽  
Golbahar Hosseini
Keyword(s):  
Serum Levels ◽  
Treated Group ◽  
Diabetic Group ◽  
Enzyme Linked Immunosorbent Assay ◽  
Diabetic Mice ◽  
Citrate Buffer ◽  
C Peptide ◽  
Tnf Α ◽  
Ifn Γ

Type 1 diabetes is a chronic autoimmune disease of beta cells in the islets of Langerhans, which are responsible for making insulin. Even with insulin therapy, inflammatory complications will develop in the long term. The present study examines changes in serum levels of interleukin (IL)-6, IL-17, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, C-peptide, Insulin as well as fasting blood sugar (FBS) in control, diabetic and diabetic treated with curcumin groups. Thirty inbred C57BL /6 mice were randomly divided into three groups of 10 mice: group A consisted of healthy mice receiving citrate buffer, group B included a group of diabetic mice, and group C was a group of diabetic mice treated with curcumin. The cytokine levels were measured in the supernatant of stimulated splenocytes using enzyme -linked immunosorbent assay (ELISA). Radioimmunoassay was used to measure insulin and c-peptide levels. The FBS was measured by an automatic glucometer device. The levels of IL-6, IL-17, and IFN-γ, as well as FBS, was significantly decreased in the treated group with curcumin compared to the diabetic group mice (p<0.05). TNF-α levels were also low, but the difference was not significant. IL-10, plasma C-peptide, and insulin significantly increased in the supernatant of stimulated splenocytes of treated diabetic group than in the diabetic group (p<0/05). According to the results, this study supports the anti-diabetic and anti-inflammatory effects of curcumin; however, more studies are needed to investigate theeffects of curcumin and the dose-response relationship in this disease.  

scholarly journals Bacterial Lipoprotein-Based Vaccines Induce Tumor Necrosis Factor-Dependent Type 1 Protective Immunity against Leishmania major

2002 ◽  
Vol 70 (1) ◽  
pp. 240-248 ◽  
Author(s):  
Javier Cote-Sierra ◽  
Amin Bredan ◽  
Carmen M. Toldos ◽  
Benoit Stijlemans ◽  
Lea Brys ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Necrosis Factor ◽  
Immune Responses ◽  
Tumor Necrosis ◽  
Leishmania Major ◽  
Rational Approach ◽  
Tnf Α ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Immunity against Leishmania major requires rapid induction of a type 1 immune response in which tumor necrosis factor alpha (TNF-α) plays an essential role. Hence, vaccination strategies that simulate the protective immune response found in hosts that have recovered from natural infection provide a rational approach to combat leishmaniasis. One method for optimizing the qualitative and quantitative immune responses after vaccination is to use an adjuvant. In this study we demonstrate that the OprI lipoprotein (L-OprI) from Pseudomonas aeruginosa induces a long-term cellular (gamma interferon [IFN-γ]) and humoral (immunoglobulin G2a) type 1 immune response against a truncated 32-kDa version (COOHgp63) of the 63-kDa major cell surface glycoprotein gp63. By contrast, immunization with COOHgp63 either fused to OprI nonlipoprotein or with no adjuvant did not result in the induction of type 1 immune responses. The adjuvanticity of L-OprI is strongly dependent on its capacity to induce TNF-α, since generation of type 1 immune responses is clearly delayed and impaired in TNF-α−/− mice. Vaccination with L-OprICOOHgp63 fusion protein protected BALB/c mice against L. major infection for at least 19 weeks. Vaccinated mice were largely free of lesions or clearly controlled lesion size on termination of the experiment. The control of disease progression in mice vaccinated with L-OprICOOHgp63 was associated with enhancement of antigen-specific IFN-γ production. These data indicate that bacterial lipoproteins constitute appropriate adjuvants to include in vaccines against diseases in which type 1 immune responses are important for protection.

scholarly journals Primary herpes simplex virus type 1 infection of the eye triggers similar immune responses in the cornea and the skin of the eyelids

2002 ◽  
Vol 83 (7) ◽  
pp. 1579-1590 ◽  
Author(s):  
Thomas H. Stumpf ◽  
Rachel Case ◽  
Carolyn Shimeld ◽  
David L. Easty ◽  
Terry J. Hill
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Disease Process ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

Herpetic stromal keratitis (HSK) and blepharoconjunctivitis in humans are thought partly to result from immunopathological responses to herpes simplex virus type 1 (HSV-1). The corneas of NIH mice were inoculated with HSV-1 (strain McKrae) and mice were examined for signs of disease and infection on days 1, 4, 7, 10, 14 and 21. The eyes and eyelids of infected and control mice were processed for immunohistochemistry and double stained for viral antigens and one of the following cell surface markers (Gr-1, F4/80, CD4, CD8, CD45R or MHC class II) or one of the following cytokines (IL-2, IL-4, IL-6, IL-10, IL-12 or IFN-γ). All infected mice developed signs of HSK by day 4 and blepharitis by day 7 and these both persisted until day 21, when signs of resolution where apparent. Virus was detected during the first week of infection and became undetectable by day 10. Large numbers of Gr-1+ cells (neutrophils) infiltrated infected corneas and eyelids in areas of viral antigen and CD4+ T cells increased significantly in number after virus clearance. In both sites, the predominant cytokines were IL-6, IL-10, IL-12 and IFN-γ, with few IL-2+ and IL-4+ cells. These observations suggest that the immune responses in the cornea are similar to those in the eyelids but, overall, the responses are not clearly characterized as either Th1 or Th2. In both sites, the neutrophil is the predominant infiltrating cell type and is a likely source of the cytokines observed and a major effector of the disease process.

scholarly journals Induction of Neutralizing Antibodies and Gag-Specific Cellular Immune Responses to an R5 Primary Isolate of Human Immunodeficiency Virus Type 1 in Rhesus Macaques

2001 ◽  
Vol 75 (13) ◽  
pp. 5879-5890 ◽  
Author(s):  
David C. Montefiori ◽  
Jeffrey T. Safrit ◽  
Shari L. Lydy ◽  
Ashley P. Barry ◽  
Miroslawa Bilska ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Cellular Immune Responses ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Cellular Immune ◽  
Hiv 1

ABSTRACT The ability to generate antibodies that cross-neutralize diverse primary isolates is an important goal for human immunodeficiency virus type 1 (HIV-1) vaccine development. Most of the candidate HIV-1 vaccines tested in humans and nonhuman primates have failed in this regard. Past efforts have focused almost entirely on the envelope glycoproteins of a small number of T-cell line-adapted strains of the virus as immunogens. Here we assessed the immunogenicity of noninfectious virus-like particles (VLP) consisting of Gag, Pro (protease), and Env from R5 primary isolate HIV-1Bx08. Immunogens were delivered to rhesus macaques in the form of either purified VLP, recombinant DNA and canarypox (ALVAC) vectors engineered to express VLP, or a combination of these products. Seroconversion to Gag and Pro was detected in all of the immunized animals. Antibodies that could neutralize HIV-1Bx08 were detected in animals that received (i) coinoculations with DNABx08 and VLPBx08, (ii) DNABx08 followed by ALVACBx08 boosting, and (iii) VLPBx08 alone. The neutralizing antibodies were highly strain specific despite the fact that they did not appear to be directed to linear epitopes in the V3 loop. Virus-specific cellular immune responses also were generated, as judged by the presence of Gag-specific gamma interferon (IFN-γ)-producing cells. These cellular immune responses required the inclusion of DNABx08 in the immunization modality, since few or no IFN-γ-producing cells were detected in animals that received either VLPBx08 or ALVACBx08 alone. The results demonstrate the feasibility of generating neutralizing antibodies and cellular immune responses that target an R5 primary HIV-1 isolate by vaccination in primates.

scholarly journals Induction of IL-12p40 and type 1 immunity by Toxoplasma gondii in the absence of the TLR-MyD88 signaling cascade

2021 ◽  
Vol 17 (10) ◽  
pp. e1009970
Author(s):  
Lindsay M. Snyder ◽  
Claire M. Doherty ◽  
Heather L. Mercer ◽  
Eric Y. Denkers
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Immune Responses ◽  
Myeloid Cell ◽  
Lymphoid Cells ◽  
Type I ◽  
Compensatory Response ◽  
Ifn Γ

Toxoplasma gondii is an orally acquired pathogen that induces strong IFN-γ based immunity conferring protection but that can also be the cause of immunopathology. The response in mice is driven in part by well-characterized MyD88-dependent signaling pathways. Here we focus on induction of less well understood immune responses that do not involve this Toll-like receptor (TLR)/IL-1 family receptor adaptor molecule, in particular as they occur in the intestinal mucosa. Using eYFP-IL-12p40 reporter mice on an MyD88-/- background, we identified dendritic cells, macrophages, and neutrophils as cellular sources of MyD88-independent IL-12 after peroral T. gondii infection. Infection-induced IL-12 was lower in the absence of MyD88, but was still clearly above noninfected levels. Overall, this carried through to the IFN-γ response, which while generally decreased was still remarkably robust in the absence of MyD88. In the latter mice, IL-12 was strictly required to induce type I immunity. Type 1 and type 3 innate lymphoid cells (ILC), CD4+ T cells, and CD8+ T cells each contributed to the IFN-γ pool. We report that ILC3 were expanded in infected MyD88-/- mice relative to their MyD88+/+ counterparts, suggesting a compensatory response triggered by loss of MyD88. Furthermore, bacterial flagellin and Toxoplasma specific CD4+ T cell populations in the lamina propria expanded in response to infection in both WT and KO mice. Finally, we show that My88-independent IL-12 and T cell mediated IFN-γ production require the presence of the intestinal microbiota. Our results identify MyD88-independent intestinal immune pathways induced by T. gondii including myeloid cell derived IL-12 production, downstream type I immunity and IFN-γ production by ILC1, ILC3, and T lymphocytes. Collectively, our data reveal an underlying network of immune responses that do not involve signaling through MyD88.

scholarly journals Localized and Systemic Immune Responses against SARS-CoV-2 Following Mucosal Immunization

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 132
Author(s):  
Shaswath S. Chandrasekar ◽  
Yashdeep Phanse ◽  
Rachel E. Hildebrand ◽  
Mostafa Hanafy ◽  
Chia-Wei Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Vaccine Strategy ◽  
Immunization Strategy ◽  
Global Pandemic ◽  
The Usa ◽  
Ifn Γ ◽  
Polyfunctional T Cells

The rapid transmission of SARS-CoV-2 in the USA and worldwide necessitates the development of multiple vaccines to combat the COVID-19 global pandemic. Previously, we showed that a particulate adjuvant system, quil-A-loaded chitosan (QAC) nanoparticles, can elicit robust immunity combined with plasmid vaccines when used against avian coronavirus. Here, we report on the immune responses elicited by mucosal homologous plasmid and a heterologous immunization strategy using a plasmid vaccine and a Modified Vaccinia Ankara (MVA) expressing SARS-CoV-2 spike (S) and nucleocapsid (N) antigens. Only the heterologous intranasal immunization strategy elicited neutralizing antibodies against SARS-CoV-2 in serum and bronchoalveolar lavage of mice, suggesting a protective vaccine. The same prime/boost strategy led to the induction of type 1 and type 17 T-cell responses and polyfunctional T-cells expressing multiple type 1 cytokines (e.g., IFN-γ, TNFα, IL-2) in the lungs and spleens of vaccinated mice. In contrast, the plasmid homologous vaccine strategy led to the induction of local mono and polyfunctional T-cells secreting IFN-γ. Outcomes of this study support the potential of QAC-nano vaccines to elicit significant mucosal immune responses against respiratory coronaviruses.

scholarly journals CD8 T Cells in Innate Immune Responses: Using STAT4-Dependent but Antigen-Independent Pathways to Gamma Interferon during Viral Infection

mBio ◽  
2014 ◽  
Vol 5 (5) ◽  
Author(s):  
Jenny E. Suarez-Ramirez ◽  
Margarite L. Tarrio ◽  
Kwangsin Kim ◽  
Delia A. Demers ◽  
Christine A. Biron
Keyword(s):  
Innate Immunity ◽  
T Cells ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Gamma Interferon ◽  
Innate Immune ◽  
Interleukin 12 ◽  
Innate Immune Responses ◽  
Ifn Γ

ABSTRACT The cytokine gamma interferon (IFN-γ), with antimicrobial and immunoregulatory functions, can be produced by T cells following stimulation through their T cell receptors (TCRs) for antigen. The innate cytokines type 1 IFNs and interleukin-12 (IL-12) can also stimulate IFN-γ production by natural killer (NK) but not naive T cells. High basal expression of signal transducer and activator of transcription 4 (STAT4), used by type 1 IFN and IL-12 to induce IFN-γ as well as CD25, contributes to the NK cell responses. During acute viral infections, antigen-specific CD8 T cells are stimulated to express elevated STAT4 and respond to the innate factors with IFN-γ production. Little is known about the requirements for cytokine compared to TCR stimulation. Primary infections of mice with lymphocytic choriomeningitis virus (LCMV) demonstrated that although the elicited antigen-specific CD8 T cells acquired STAT4-dependent innate cytokine responsiveness for IFN-γ and CD25 induction ex vivo, TCR stimulation induced these through STAT4-independent pathways. During secondary infections, LCMV-immune CD8 T cells had STAT4-dependent IFN-γ expression at times of innate cytokine induction but subsequently expanded through STAT4-independent pathways. At times of innate cytokine responses during infection with the antigen-distinct murine cytomegalovirus virus (MCMV), NK and LCMV-immune CD8 T cells both had activation of pSTAT4 and IFN-γ. The T cell IFN-γ response was STAT4 and IL-12 dependent, but antigen-dependent expansion was absent. By dissecting requirements for STAT4 and antigen, this work provides novel insights into the endogenous regulation of cytokine and proliferative responses and demonstrates conditioning of innate immunity by experience. IMPORTANCE Understanding the regulation and function of adaptive immunity is key to the development of new and improved vaccines. Its CD8 T cells are activated through antigen-specific receptors to contribute to long-lasting immunity after natural infections or purposeful immunization. The antigen-receptor pathway of stimulation can lead to production of gamma interferon (IFN-γ), a cytokine having both direct antimicrobial and immunoregulatory functions. Natural killer cells can also produce IFN-γ in response to the innate cytokines type 1 IFNs and/or interleukin-12. This work demonstrates that CD8 T cells acquire parallel responsiveness to innate cytokine signaling for IFN-γ expression during their selection and development and maintain this capability to participate in innate immune responses as long-lived memory cells. Thus, CD8 T cells are conditioned to play a role in innate immunity, and their presence under immune conditions has the potential to regulate resistance to either secondary challenges or primary infections with unrelated agents.

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