Defects in T-cell–mediated immunity to influenza virus in murine Wiskott-Aldrich syndrome are corrected by oncoretroviral vector–mediated gene transfer into repopulating hematopoietic cells

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3108-3116 ◽  
Author(s):  
Ted S. Strom ◽  
Stephen J. Turner ◽  
Samita Andreansky ◽  
Haiyan Liu ◽  
Peter C. Doherty ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Response ◽  
Bone Marrow Cells ◽  
T Cell Response ◽  
Lymphoid Cells ◽  
Wiskott Aldrich Syndrome ◽  
Marrow Cells

AbstractThe Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by immune dysfunction, thrombocytopenia, and eczema. We used a murine model created by knockout of the WAS protein gene (WASP) to evaluate the potential of gene therapy for WAS. Lethally irradiated, male WASP— animals that received transplants of mixtures of wild type (WT) and WASP— bone marrow cells demonstrated enrichment of WT cells in the lymphoid and myeloid lineages with a progressive increase in the proportion of WT T-lymphoid and B-lymphoid cells. WASP— mice had a defective secondary T-cell response to influenza virus which was normalized in animals that received transplants of 35% or more WT cells. The WASP gene was inserted into WASP— bone marrow cells with a bicistronic oncoretroviral vector also encoding green fluorescent protein (GFP), followed by transplantation into irradiated male WASP— recipients. There was a selective advantage for gene-corrected cells in multiple lineages. Animals with higher proportions of GFP+ T cells showed normalization of their lymphocyte counts. Gene-corrected, blood T cells exhibited full and partial correction, respectively, of their defective proliferative and cytokine secretory responses to in vitro T-cell–receptor stimulation. The defective secondary T-cell response to influenza virus was also improved in gene-corrected animals.

The Orphan Nuclear Receptor NR2F6 Is a Novel Negative Regulator of T-Cell Development.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 915-915
Author(s):  
Christine V. Ichim ◽  
Dzana Dervovic ◽  
Juan Carlo Zuniga-Pflucker ◽  
Richard A. Wells
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Progenitor Cells ◽  
Nuclear Receptor ◽  
Bone Marrow Cells ◽  
Orphan Nuclear Receptor ◽  
Over Expression ◽  
Competitive Disadvantage ◽  
Marrow Cells

Abstract Abstract 915 The orphan nuclear receptor NR2F6 is a mammalian homologue of the Drosophila seven-up gene that plays key roles in decisions of cell fate in neuroblast and retinal cells. We have previously described a novel role for NR2F6 in decisions of cell fate of mammalian haematopoietic cells of the myeloid cell lineage. We have shown that over-expression of NR2F6 in bone marrow cells impairs differentiation and extends the proliferative capacity of myeloid and early progenitor cells eventually leading to acute myeloid leukaemia (AML), while silencing of NR2F6 expression in AML cell lines causes terminal differentiation and apoptosis. A role of NR2F6 in lymphopoiesis has yet to be identified. Here we describe for the first time a role for NR2F6 in the specification of lymphoid cells. NR2F6 expression is heterogeneous throughout the haematopoietic hierarchy, with expression being highest in long-term repopulating HSCs and generally declining with the differentiation of progenitor cells. We report that over-expression of NR2F6 abrogates the developmental program necessary for T-cell lymphopoiesis. We assessed the effects of NR2F6 on lymphopoiesis in vivo by competitive bone marrow transplantation of NR2F6-IRES-GFP or GFP retrovirally transduced grafts (n=43). Competitive repopulation of lethally irradiated murine hosts with GFP transduced bone marrow cells resulted in successful engraftment and T-cell development, with GFP+ T-cells present in the thymus, and periphery at rates comparable to the percent marked cells in the original graft. However over-expression of NR2F6 placed developing T-cells at a dramatic competitive disadvantage. Six weeks post transplant the proportion of CD3+ cells derived from NR2F6 transduced bone marrow cells was greatly diminished relative to control (more than 10 fold), while at 12 weeks post-transplant we observed an abrogation of CD3+ cells derived from NR2F6 transduced T-cells (with the percentage of NR2F6 transduced CD3+ cells being comparable to staining with IgG control) in both the thymus and periphery. This stark competitive disadvantage was observed in all recipients of NR2F6 transduced grafts. We confirmed that this is not a phenomenon specific to the marker CD3 by analysing a portion of the animals for expression of CD4 and CD8, which again showed a lack of mature t-cells. In a second series of bone marrow transplants, cells transduced with NR2F6 or GFP were purified by fluorescence-activated cell sorting and grafts of 100% transduced cells were transferred by tail vein injection into lethally irradiated recipients. Animals transplanted with NR2F6 transduced bone marrow demonstrated a gross decrease in their thymic size and cellularity (∼10 fold decrease, n=17). Furthermore, the thymus of NR2F6 transduced animals contained a larger proportion of non-transduced, GFP negative residual haematopoietic cells than the vector control animals, corroborating the competitive disadvantage that NR2F6 transduced bone marrow cells face in the thymus. As observed in our previous experiments these animals demonstrated a gross reduction in the proportion of CD3+ cells in the thymus, spleen, lymph nodes and peripheral blood. To rule out the possibility that over-expression of NR2F6 is preventing the trafficking of progenitor cells to the thymus we differentiated NR2F6 or GFP transduced haematopoietic stem cells (lin-,c-kit+,sca-1+) into T-cells in vitro on OP9-DL1 cells. We observed a drastic reduction in the number of cells generated from NR2F6 transduced stem/progenitor cells (>50 fold at day 23), suggesting that expression of NR2F6 greatly impairs T-cell development. Mechanistically, others have shown that NR2F6 functions as a transcriptional repressor inhibiting the transactivating ability of genes such as Runx1. We conjecture that in lymphoid progenitors as well NR2F6 functions as a transcriptional repressor preventing the activation of pathways necessary for T-cell survival, proliferation and lymphopoiesis. Taken together, these data establish that the orphan nuclear receptor NR2F6 is a novel negative regulator of T-cell lymphopoiesis, and demonstrate that down-regulation of NR2F6 is important for the survival and proliferation of T-cell progenitors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Role of viral infectivity in the induction of influenza virus-specific cytotoxic T cells.

1978 ◽  
Vol 147 (4) ◽  
pp. 1236-1252 ◽  
Author(s):  
T J Braciale ◽  
K L Yap
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Response ◽  
Infectious Virus ◽  
Cytotoxic T Cells ◽  
T Cell Response ◽  
Cytotoxic T Cell

This report examines the requirement for infectious virus in the induction of influenza virus-specific cytotoxic T cells. Infectious influenza virus was found to be highly efficient at generating both primary and secondary cytotoxic T-cell response in vivo. Inactivated influenza virus however, failed to stimulate a detectable cytotoxic T-cell response in vivo even at immunizing doses 10(5)-10(6)-fold higher than the minimum stimulatory dose of infectious virus. Likewise inactivated virus failed to sensitize target cells for T cell-mediated lysis in vitro but could stimulate a specific cytotoxic response from primed cells in vitro. Possible requirements for the induction of virus-specific cytotoxic T-cell responses are discussed in light of these observations and those of other investigators.

scholarly journals Production of auto-antiidiotypic antibody during the normal immune response. VII. Analysis of the cellular basis for the increased auto-antiidiotype antibody production by aged mice.

1983 ◽  
Vol 157 (5) ◽  
pp. 1635-1645 ◽  
Author(s):  
E A Goidl ◽  
J W Choy ◽  
J J Gibbons ◽  
M E Weksler ◽  
G J Thorbecke ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Bone Marrow Cells ◽  
Aged Mice ◽  
Old Mice ◽  
Marrow Cells ◽  
Young Mice

We have previously shown that old mice produce more hapten-augmentable plaque-forming cells (PFC) than do young animals, suggesting a greater auto-antiidiotype antibody (auto anti-Id) component in their immune response. In the present studies this is confirmed serologically. The marked auto-anti-Id response of aged mice can be transferred to lethally irradiated young recipients with spleen but not bone marrow cells from old donors, suggesting that it is an intrinsic property of their peripheral B cell population and that the distribution of Id arising from the bone marrow of old and young mice is similar. In contrast with young mice the auto-anti-Id response of old animals is relatively T cell-independent and old donors do not show an increase in their ability to transfer an auto-anti-Id response after priming with TNP-F. These observations suggest that old mice behave as if already primed for auto-anti-Id production. Irradiated mice reconstituted with bone marrow cells from either young or old donors together with splenic T cells from old donors generate a relatively large auto-anti-Id response, whereas mice reconstituted with bone marrow from either young or old donors together with splenic T cells from young donors produce few hapten-augmentable PFC. It is suggested that differences in Id expression and auto-anti-Id production are the consequences of the interaction of Id (and anti-Id) arising from the marrow with anti-Id (and Id) present in the peripheral T cell population which serves as a repository of information about shifts in Id distribution, resulting from lifelong interactions with environmental and self-antigens.

scholarly journals Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 841-851 ◽  
Author(s):  
Elaine M. Sloand ◽  
Lori Mainwaring ◽  
Monika Fuhrer ◽  
Shakti Ramkissoon ◽  
Antonio M. Risitano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Growth ◽  
Myelodysplastic Syndrome ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Cell Contact ◽  
Trisomy 8 ◽  
Marrow Cells

AbstractClinical observations and experimental evidence link bone marrow failure in myelodysplastic syndrome (MDS) with a T cell–dominated autoimmune process. Immunosuppressive therapy is effective in improving cytopenias in selected patients. Trisomy 8 is a frequent cytogenetic abnormality in bone marrow cells in patients with MDS, and its presence has been associated anecdotally with good response to immunotherapy. We studied 34 patients with trisomy 8 in bone marrow cells, some of whom were undergoing treatment with antithymocyte globulin (ATG). All had significant CD8+ T-cell expansions of one or more T-cell receptor (TCR) Vβ subfamilies, as measured by flow cytometry; expanded subfamilies showed CDR3 skewing by spectratyping. Sorted T cells of the expanded Vβ subfamilies, but not of the remaining subfamilies, inhibited trisomy 8 cell growth in short-term hematopoietic culture. The negative effects of Vβ-expanded T cells were inhibited by major histocompatibility complex (MHC) class 1 monoclonal antibody (mAb) and Fas antagonist and required direct cell-to-cell contact. Sixty-seven percent of patients who had de novo MDS with trisomy 8 as the sole karyotypic abnormality responded to ATG with durable reversal of cytopenias and restoration of transfusion independence, with stable increase in the proportion of trisomy 8 bone marrow cells and normalization of the T-cell repertoire. An increased number of T cells with apparent specificity for trisomy 8 cells is consistent with an autoimmune pathophysiology in trisomy 8 MDS.

scholarly journals Thymopoietic and Bone Marrow Response to Murine Pneumocystis Pneumonia

2011 ◽  
Vol 79 (5) ◽  
pp. 2031-2042 ◽  
Author(s):  
Xin Shi ◽  
Ping Zhang ◽  
Gregory D. Sempowski ◽  
Judd E. Shellito
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Host Defense ◽  
Bone Marrow Cells ◽  
Central Memory ◽  
Jnk Pathway ◽  
Content Type ◽  
Enhanced Production ◽  
Marrow Cells

ABSTRACTCD4+T cells play a key role in host defense againstPneumocystisinfection. To define the role of naïve CD4+T cell production through the thymopoietic response in host defense againstPneumocystisinfection,Pneumocystis murinainfection in the lung was induced in adult male C57BL/6 mice with and without prior thymectomy.Pneumocystisinfection caused a significant increase in the number of CCR9+multipotent progenitor (MPP) cells in the bone marrow and peripheral circulation, an increase in populations of earliest thymic progenitors (ETPs) and double negative (DN) thymocytes in the thymus, and recruitment of naïve and total CD4+T cells into the alveolar space. The level of murine signal joint T cell receptor excision circles (msjTRECs) in spleen CD4+cells was increased at 5 weeks post-Pneumocystisinfection. In thymectomized mice, the numbers of naïve, central memory, and total CD4+T cells in all tissues examined were markedly reduced followingPneumocystisinfection. This deficiency of naïve and central memory CD4+T cells was associated with delayed pulmonary clearance ofPneumocystis. Extracts ofPneumocystisresulted in an increase in the number of CCR9+MPPs in the cultured bone marrow cells. Stimulation of cultured bone marrow cells with ligands to Toll-like receptor 2 ([TLR-2] zymosan) and TLR-9 (ODN M362) each caused a similar increase in CCR9+MPP cells via activation of the Jun N-terminal protein kinase (JNK) pathway. These results demonstrate that enhanced production of naïve CD4+T lymphocytes through the thymopoietic response and enhanced delivery of lymphopoietic precursors from the bone marrow play an important role in host defense againstPneumocystisinfection.

scholarly journals CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to promote tolerance

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3475-3484 ◽  
Author(s):  
Josef Kurtz ◽  
Forum Raval ◽  
Casey Vallot ◽  
Jayden Der ◽  
Megan Sykes
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Bone Marrow Cells ◽  
Antigen Presenting Cells ◽  
Cd4 T Cell ◽  
Cell Tolerance ◽  
Antigen Presenting ◽  
Marrow Cells

Abstract Although the inhibitory receptor CTLA-4 (CD152) has been implicated in peripheral CD4 T-cell tolerance, its mechanism of action remains poorly defined. We analyzed mechanisms of CD4 cell tolerance in a model of tolerance induction involving establishment of mixed hematopoietic chimerism in recipients of fully MHC-mismatched allogeneic bone marrow cells with anti-CD154 mAb. Animals lacking CD80 and CD86 failed to achieve chimerism. We detected no T cell–intrinsic requirement for CD28 for chimerism induction. However, a CD4 T cell–intrinsic signal through CTLA-4 was shown to be essential within the first 48 hours of exposure to alloantigen for the establishment of tolerance and mixed chimerism. This signal must be provided by a recipient CD80/86+ non–T-cell population. Donor CD80/86 expression was insufficient to achieve tolerance. Together, our findings demonstrate a surprising role for interactions of CTLA-4 expressed by alloreactive peripheral CD4 T cells with CD80/86 on recipient antigen-presenting cells (APCs) in the induction of early tolerance, suggesting a 3-cell tolerance model involving directly alloreactive CD4 cells, donor antigen-expressing bone marrow cells, and recipient antigen-presenting cells. This tolerance is independent of regulatory T cells and culminates in the deletion of directly alloreactive CD4 T cells.

scholarly journals Differential Antigen Presentation Regulates the Changing Patterns of CD8+ T Cell Immunodominance in Primary and Secondary Influenza Virus Infections

2003 ◽  
Vol 198 (3) ◽  
pp. 399-410 ◽  
Author(s):  
Sherry R. Crowe ◽  
Stephen J. Turner ◽  
Shannon C. Miller ◽  
Alan D. Roberts ◽  
Rachel A. Rappolo ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Virus Infection ◽  
Antigen Presentation ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Influenza Virus Infection ◽  
Cd8 T Cell ◽  
T Cell Response

The specificity of CD8+ T cell responses can vary dramatically between primary and secondary infections. For example, NP366–374/Db- and PA224–233/Db-specific CD8+ T cells respond in approximately equal numbers to a primary influenza virus infection in C57BL/6 mice, whereas NP366–374/Db-specific CD8+ T cells dominate the secondary response. To investigate the mechanisms underlying this changing pattern of immunodominance, we analyzed the role of antigen presentation in regulating the specificity of the T cell response. The data show that both dendritic and nondendritic cells are able to present the NP366–374/Db epitope, whereas only dendritic cells effectively present the PA224–233/Db epitope after influenza virus infection, both in vitro and in vivo. This difference in epitope expression favored the activation and expansion of NP366–374/Db-specific CD8+ memory T cells during secondary infection. The data also show that the immune response to influenza virus infection may involve T cells specific for epitopes, such as PA224–233/Db, that are poorly expressed at the site of infection. In this regard, vaccination with the PA224–233 peptide actually had a detrimental effect on the clearance of a subsequent influenza virus infection. Thus, differential antigen presentation impacts both the specificity of the T cell response and the efficacy of peptide-based vaccination strategies.

Adoptive Transfer of Primed T Cells Mediates a Graft-Versus-Leukemia Effect against Pediatric ALL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1340-1340
Author(s):  
Haiying Qin ◽  
Jessica PE Davis ◽  
Christian M. Capitini ◽  
Terry J Fry
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Cell Response ◽  
T Cell Response ◽  
The Poor ◽  
Graft Versus Leukemia ◽  
Pediatric All

Abstract Abstract 1340 Poster Board I-362 Background Pediatric Acute Lymphoblastic Leukemia (ALL) is the most common childhood malignancy. While current upfront therapy will cure over 80% of patients, treating relapse remains a major challenge. Blood or marrow transplantation (BMT) offers a therapeutic option but approximately 50% of patients undergoing BMT will not survive with relapse being the most common cause of death. Donor lymphocyte infusions (DLIs) have demonstrated efficacy in myeloid leukemia but are much less effective for ALL. Thus, we explored strategies to improve on the potency of the graft versus leukemia response against pediatric ALL using a murine model developed from E2a-PBX1 transgenic mice that express a recurring translocation t(1;19) present in approximately 5% of all pediatric ALL. Methods E2a-PBX1 was administered intravenously (IV). Irradiated E2a-PBX1 was administered intraperitoneally for immunization both in the vaccine protection model and to prime DLI donors in the BMT models. Transplanted mice were lethally irradiated and given T-cell-depleted bone marrow cells followed by purified T cells as a DLI. In the syngeneic model, C57Bl/6 mice were used as both recipients and donors so that both donor cells were syngeneic to the tumor. In the allogeneic model, C57Bl/6 recipients received bone marrow and T cells from MHC-matched C3H.SW donors that are minor antigen-mismatched to both tumor and recipient, analogous to the clinical BMT setting. Results We confirmed that E2a-PBX1 is a pre-B cell ALL that expresses B220, BP-1, CD43 and the alpha chain of the IL-7 receptor. The distribution of leukemia is similar to that observed in humans with bone marrow, lymph node, liver, spleen and central nervous system involvement confirmed by necropsy and imaging following injection of luciferase-expressing cells. Amazingly, E2a-PBX1 is lethal with as few as with as 1×102 cells (5/5 mice) in sublethally irradiated mice (250 cGy) and 1×104 cells in unirradiated mice (4/5 mice). Vaccination prior to tumor challenge protected 90-100% of mice from leukemia development. Mice that successfully rejected E2a-PBX1 were protected against rechallenge with a higher cell dose. Antibody depletion of either CD4+ or CD8+ T cells did not affect vaccine-mediated protection. However, depletion of both CD4+ and CD8+ T cells significantly diminished vaccine efficacy (n=7/group, p=0.0063). Interestingly, although data from killer inhibitory receptor (KIR) mismatched BMT would suggest that NK cells are less potent in ALL than in AML, antibody depletion of NK cells with either anti-asialo GM1 or anti-NK1.1 also had a significant impact on survival in our model. We next tested the therapeutic effect of purified T cells injected IV after E2aPBX1 injection. Administration of naive T cells (6×106) following syngeneic BMT was not effective at treating E2a-PBX1. The presence of minor antigen differences between donor T cells and tumor following allogeneic BMT did not increase the efficacy of naïve T cells consistent with the poor response rate to DLI in patients with ALL. However, primed T cell DLI from a donor immunized by irradiated E2a-PBX1 resulted in a statistically significant prolongation of survival in both syngeneic (p=.0067) and allogeneic (p=.008) BMT models. Conclusion: When administered in our allogeneic transplant model, E2a-PBX1 can be used to model relapse of pediatric ALL post-BMT. Naïve T cells (analogous to DLI given post-relapse in the clinic) were ineffective at treating ALL our model. However, priming of the DLI significantly prolonged survival demonstrating that the poor efficacy of DLI in ALL is not due to an inherent resistance of ALL to a T cell response. Our data supports the use of T cells to treat pediatric ALL relapse post-BMT but suggests manipulation of the T cell response will be required. Disclosures No relevant conflicts of interest to declare.

scholarly journals Gamma Interferon Regulates Contraction of the Influenza Virus-Specific CD8 T Cell Response and Limits the Size of the Memory Population

2013 ◽  
Vol 87 (23) ◽  
pp. 12510-12522 ◽  
Author(s):  
Nayana Prabhu ◽  
Adrian W. Ho ◽  
Kenneth H. S. Wong ◽  
Paul Edward Hutchinson ◽  
Yen Leong Chua ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Population ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Memory Cell ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Ifn Γ

The factors that regulate the contraction of the CD8 T cell response and the magnitude of the memory cell population against localized mucosal infections such as influenza are important for generation of efficient vaccines but are currently undefined. In this study, we used a mouse model of influenza to demonstrate that the absence of gamma interferon (IFN-γ) or IFN-γ receptor 1 (IFN-γR1) leads to aberrant contraction of antigen-specific CD8 T cell responses. The increased accumulation of the effector CD8 T cell population was independent of viral load. Reduced contraction was associated with an increased fraction of CD8 T cells expressing the interleukin-7 receptor (IL-7R) at the peak of the response, resulting in enhanced numbers of memory/memory precursor cells in IFN-γ−/−and IFN-γR−/−compared to wild-type (WT) mice. Blockade of IL-7 within the lungs of IFN-γ−/−mice restored the contraction of influenza virus-specific CD8 T cells, indicating that IL-7R is important for survival and is not simply a consequence of the lack of IFN-γ signaling. Finally, enhanced CD8 T cell recall responses and accelerated viral clearance were observed in the IFN-γ−/−and IFN-γR−/−mice after rechallenge with a heterologous strain of influenza virus, confirming that higher frequencies of memory precursors are formed in the absence of IFN-γ signaling. In summary, we have identified IFN-γ as an important regulator of localized viral immunity that promotes the contraction of antigen-specific CD8 T cells and inhibits memory precursor formation, thereby limiting the size of the memory cell population after an influenza virus infection.

scholarly journals Protein Vaccination Directs the CD4+ T Cell Response toward Shared Protective Epitopes That Can Be Recalled after Influenza Virus Infection

2019 ◽  
Vol 93 (20) ◽  
Author(s):  
Ajitanuj Rattan ◽  
Katherine A. Richards ◽  
Zackery A. G. Knowlden ◽  
Andrea J. Sant
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Virus Infection ◽  
Specific Antibody ◽  
Cell Response ◽  
Protective Immunity ◽  
Influenza Virus Infection ◽  
T Cell Response ◽  
Protein Vaccine

ABSTRACT Vaccination is widely used to generate protective immunity against influenza virus. CD4+ T cells contribute in diverse ways to protective immunity, most notably, in the provision of help for the production of neutralizing antibodies. Several recent reports have suggested that influenza virus infection elicits CD4+ T cells whose specificity only partially overlaps that of T cells elicited by vaccination. This finding has raised serious concerns regarding the utility of currently licensed inactivated influenza virus vaccines and novel protein-based vaccines. Here, using controlled animal models that allowed a broad sampling of the CD4+ T cell repertoire, we evaluated protein vaccine- versus infection-generated CD4+ T cell epitopes. Our studies revealed that all the infection-elicited CD4+ T cell epitope specificities are also elicited by protein vaccination, although the immunodominance hierarchies can differ. Finally, using a reverse-engineered influenza virus and a heterologous protein vaccination and infection challenge strategy, we show that protein vaccine-elicited CD4+ memory T cells are recalled and boosted after infection and provide early help to accelerate hemagglutinin (HA)-specific antibody responses. The early CD4+ T cell response and HA-specific antibody production are associated with lowered viral titers during the infection challenge. Our data lend confidence to the ability of current protein-based vaccines to elicit influenza virus-specific CD4+ T cells that can potentiate protective immunity upon influenza virus infection. IMPORTANCE Most current and new influenza vaccine candidates consist of a single influenza virus protein or combinations of influenza virus proteins. For these vaccines to elicit CD4+ T cells that can be recalled after infection, the peptide epitopes should be shared between the two modes of confrontation. Recently, questions regarding the relatedness of epitope selection by influenza virus infection and protein vaccination have been raised. However, the studies reported here show that the specificity of CD4+ T cells elicited by protein-based vaccines overlaps that of T cells elicited by infection and that CD4+ T cells primed by protein vaccines are recalled and contribute to protection of the host from a future infection.

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