The circadian clock of CD8 T cells modulates their early response to vaccination and the rhythmicity of related signaling pathways

Circadian variations of various aspects of the immune system have been described. However, the circadian control of T cells has been relatively unexplored. Here, we investigated the role of circadian clocks in regulating CD8 T cell response to antigen presentation by dendritic cells (DCs). The in vivo CD8 T cell response following vaccination with DCs loaded with the OVA257–264 peptide antigen (DC-OVA) leads to a higher expansion of OVA-specific T cells in response to vaccination done in the middle of the day, compared to other time points. This rhythm was dampened when DCs deficient for the essential clock gene Bmal1 were used and abolished in mice with a CD8 T cell-specific Bmal1 deletion. Thus, we assessed the circadian transcriptome of CD8 T cells and found an enrichment in the daytime of genes and pathways involved in T cell activation. Based on this, we investigated early T cell activation events. Three days postvaccination, we found higher T cell activation markers and related signaling pathways (including IRF4, mTOR, and AKT) after a vaccination done during the middle of the day compared to the middle of the night. Finally, the functional impact of the stronger daytime response was shown by a more efficient response to a bacterial challenge at this time of day. Altogether, these results suggest that the clock of CD8 T cells modulates the response to vaccination by shaping the transcriptional program of these cells and making them more prone to strong and efficient activation and proliferation according to the time of day.

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

Journal of Experimental Medicine ◽

10.1084/jem.20071135 ◽

2008 ◽

Vol 205 (3) ◽

pp. 669-684 ◽

Cited By ~ 46

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.

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Abstract 350: Synthetic Soluble MHC-I/peptide Complexes Confirm Activation of Functional Antigen-specific CD8+ T cells by Immunization With apoB-100-derived Peptide p210 in ApoE-/- Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.350 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Xiaoning Zhao ◽

Paul C Dimayuga ◽

Juliana Yano ◽

Jianchang Zhou ◽

Wai Man Lio ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Cd8 T Cell ◽

Cytolytic Activity ◽

T Cell Response ◽

Mhc I ◽

Peptide Complexes

Background: Investigations in our laboratory identified endogenous, antigen-specific CD8+ T cells reactive to apoB-100 related peptide in apoE-/- mice using fluorescent synthetic soluble MHC-I/peptide complexes called Pentamers (Pent). We hypothesized that immunization of apoE-/- mice with the apoB-100 peptide p210, which we and others have reported to reduce atherosclerosis, will result in the activation of a specific CD8+ T cell population that can be detected by Pent analysis. Methods and Results: Binding of the p210 peptide to the mouse MHC-I allele H2Kb was determined in a prior study. A p210-Pent library was generated to screen splenocytes from p210 immunized apoE-/- mice. Mice were immunized with p210 conjugated to cBSA with Alum (p210) at 7, 10 and 12 weeks of age then euthanized at 13 weeks of age. PBS and cBSA/Alum (cBSA) treatment served as controls. The screening assay identified 2 potential Pents that could discriminate the immunized mice from the controls. The Pent with the largest difference, called Pent 5, was selected for further study. Pent 5(+)CD8+ T cells in p210 immunized mice were significantly increased compared to PBS and cBSA controls (1.3±0.9% vs. 0.6±0.4% and 0.7±0.4%, respectively; P<0.05). Immunization of apoE-/- mice expressing GFP on the FoxP3 promoter showed no difference in Pent 5(+)CD8+FoxP3+ T cells. High fat diet feeding for 6 weeks did not affect Pent 5(+)CD8+ T cells compared to normal chow fed mice confirming specificity of the Pent 5(+)CD8+ T cell response to immunization. Pent 5 binding significantly reduced cytolytic activity of p210-immune CD8+ T cells compared to control (1.2±2.2% vs. 17.0±13.8%, respectively), indicating antigen-specific blocking. Pent 5(+)CD8+ T cells cultured for 21 days showed significantly higher cytolytic activity compared to Pent 5(-)CD8+ T cells (16.5±7.0% vs. 2.8±3.6%, respectively). Immunization with the p210 peptide reduced aortic atherosclerosis measured by en face oil red-o stain area compared to PBS and cBSA control groups (4.0±1.7% vs. 6.4±2.3% and 5.7±2.2%, respectively; P<0.01), confirming our previous report. Conclusion: The use of Pentamers provide clear evidence that p210 immunization results in CD8+ T cell activation with functions specific to the p210 antigen.

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Type I Interferons Regulate the Magnitude and Functionality of Mouse Polyomavirus-Specific CD8 T Cells in a Virus Strain-Dependent Manner

Journal of Virology ◽

10.1128/jvi.00199-16 ◽

2016 ◽

Vol 90 (10) ◽

pp. 5187-5199 ◽

Cited By ~ 7

Author(s):

Qingsong Qin ◽

Shwetank ◽

Elizabeth L. Frost ◽

Saumya Maru ◽

Aron E. Lukacher

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response ◽

Single Amino Acid ◽

Type I ◽

Type I Ifns ◽

Vp1 Capsid Protein

ABSTRACTMouse polyomavirus (MPyV) is a ubiquitous persistent natural mouse pathogen. A glutamic acid (E)-to-glycine (G) difference at position 91 of the VP1 capsid protein shifts the profile of tumors induced by MPyV from an epithelial to a mesenchymal cell origin. Here we asked if this tropism difference affects the MPyV-specific CD8 T cell response, which controls MPyV infection and tumorigenesis. Infection by the laboratory MPyV strain RA (VP1-91G) or a strain A2 mutant with an E-to-G substitution at VP1 residue 91 [A2(91G)] generated a markedly smaller virus-specific CD8 T cell response than that induced by A2(VP1-91E) infection. Mutant A2(91G)-infected mice showed a higher frequency of memory precursor (CD127hiKLRG1lo) CD8 T cells and a higher recall response than those of A2-infected mice. Using T cell receptor (TCR)-transgenic CD8 T cells and immunization with peptide-pulsed dendritic cells, we found that early bystander inflammation associated with A2 infection contributed to recruitment of the larger MPyV-specific CD8 T cell response. Beta interferon (IFN-β) transcripts were induced early during A2 or A2(91G) infections. IFN-β inhibited replication of A2 and A2(91G)in vitro. Using mice lacking IFN-αβ receptors (IFNAR−/−), we showed that type I IFNs played a role in controlling MPyV replicationin vivobut differentially affected the magnitude and functionality of virus-specific CD8 T cells recruited by A2 and A2(91G) viral infections. These data indicate that type I IFNs are involved in protection against MPyV infection and that their effect on the antiviral CD8 T cell response depends on capsid-mediated tropism properties of the MPyV strain.IMPORTANCEIsolates of the human polyomavirus JC virus from patients with the frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML) carry single amino acid substitutions in the domain of the VP1 capsid protein that binds the sialic acid moiety of glycoprotein/glycolipid receptors on host cells. These VP1 mutations may alter neural cell tropism or enable escape from neutralizing antibodies. Changes in host cell tropism can affect recruitment of virus-specific CD8 T cells. Using mouse polyomavirus, we demonstrate that a single amino acid difference in VP1 known to shift viral tropism profoundly affects the quantity and quality of the anti-polyomavirus CD8 T cell response and its differentiation into memory cells. These findings raise the possibility that CD8 T cell responses to infections by human polyomaviruses may be influenced by VP1 mutations involving domains that engage host cell receptors.

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Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

Journal of Virology ◽

10.1128/jvi.79.15.9419-9429.2005 ◽

2005 ◽

Vol 79 (15) ◽

pp. 9419-9429 ◽

Cited By ~ 29

Author(s):

Nicole E. Miller ◽

Jennifer R. Bonczyk ◽

Yumi Nakayama ◽

M. Suresh

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Response ◽

Viral Infections ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Cell Responses ◽

Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

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Mucosal CD8+ T cell responses induced by an MCMV based vaccine vector confer protection against influenza challenge

10.1101/494864 ◽

2018 ◽

Author(s):

Xiaoyan Zheng ◽

Jennifer Dora Oduro ◽

Julia Désirée Boehme ◽

Lisa Borkner ◽

Thomas Ebensen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Response ◽

Influenza A ◽

Clinical Medicine ◽

Cd8 T Cell ◽

T Cell Response ◽

Vaccine Vector ◽

Protective Capacity

Cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes life-long latent infection in a high percentage of the population worldwide. CMV induces the strongest and most durable CD8+ T cell response known in human clinical medicine. Due to its unique properties, the virus represents a promising candidate vaccine vector for the induction of persistent cellular immunity. To take advantage of this, we constructed a recombinant murine CMV (MCMV) expressing an MHC-I restricted epitope from influenza A virus (IAV) H1N1 within the immediate early 2 (ie2) gene. Only mice that were immunized intranasally (i.n.) were capable of controlling IAV infection, despite the greater potency of the intraperitoneally (i.p.) vaccination in inducing a systemic IAV-specific CD8+ T cell response. The protective capacity of the i.n. immunization was associated with its ability to induce IAV-specific tissue-resident memory CD8+ T (CD8TRM) cells in the lungs. Our data demonstrate that the protective effect exerted by the i.n. immunization was critically mediated by antigen-specific CD8+ T cells. CD8TRM cells promoted the induction of IFNγ and chemokines that facilitate the recruitment of antigen-specific CD8+ T cells to the lungs. Overall, our results showed that locally applied MCMV vectors could induce mucosal immunity at sites of entry, providing superior immune protection against respiratory infections.

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Development and characterization of a HCMV multiantigen therapeutic vaccine for GBM using the UNITE platform.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14565 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14565-e14565

Author(s):

Amit Adhikari ◽

Juliete Macauley ◽

Yoshimi Johnson ◽

Mike Connolly ◽

Tim Coleman ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Mouse Model ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

T Cell Response

e14565 Background: Glioblastoma (GBM) is an aggressive form of brain cancer with a median survival of 15 months which has remained unchanged despite technological advances in the standard of care. GBM cells specifically express human cytomegalovirus (HCMV) proteins providing a unique opportunity for targeted therapy. Methods: We utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to develop a multi-antigen DNA vaccine (ITI-1001) that codes for the HCMV proteins- pp65, gB and IE-1. The UNITE platform involves lysosomal targeting technology, fusing lysosome-associated protein 1 (LAMP1) with target antigens resulting in increased antigen presentation by MHC-I and II. ELISpot, flow cytometry and ELISA techniques were used to evaluate the vaccine immunogenicity and a syngeneic, orthotopic GBM mouse model that expresses HCMV proteins was used for efficacy studies. The tumor microenvironment studies were done using flow cytometry and MSD assay. Results: ITI-1001 vaccination showed a robust antigen-specific CD4 and CD8 T cell response in addition to a strong humoral response. Using GBM mouse model, therapeutic treatment of ITI-1001 vaccine resulted in ̃56% survival with subsequent long-term immunity. Investigating the tumor microenvironment showed significant CD4 T cell infiltration as well as enhanced Th1 and CD8 T cell activation. Regulatory T cells were also upregulated upon ITI-1001 vaccination and would be an attractive target to further improve this therapy. In addition, tumor burden negatively correlated with number of activated CD4 T cells (CD4 IFNγ+) reiterating the importance of CD4 activation in ITI-1001 efficacy and potentially identifying treatment responders and non-responders. Further characterization of these two groups showed high infiltration of CD3+, CD4+ and CD8+ T cells in responders compared with non- responders along with higher CD8 T cell activation. Conclusions: Thus, we show that vaccination with HCMV antigens using the ITI-1001-UNITE platform generates strong cellular and humoral immune responses, triggering significant anti-tumor activity that leads to enhanced survival in mice with GBM.

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IL4I1 Accelerates the Expansion of Effector CD8+ T Cells at the Expense of Memory Precursors by Increasing the Threshold of T-Cell Activation

Frontiers in Immunology ◽

10.3389/fimmu.2020.600012 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Marie-Line Puiffe ◽

Aurélie Dupont ◽

Nouhoum Sako ◽

Jérôme Gatineau ◽

José L. Cohen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Cell Clone ◽

Cd8 T Cell ◽

Lymphocytic Choriomeningitis ◽

T Cell Clone

IL4I1 is an immunoregulatory enzyme that inhibits CD8 T-cell proliferation in vitro and in the tumoral context. Here, we dissected the effect of IL4I1 on CD8 T-cell priming by studying the differentiation of a transgenic CD8 T-cell clone and the endogenous repertoire in a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection. Unexpectedly, we show that IL4I1 accelerates the expansion of functional effector CD8 T cells during the first several days after infection and increases the average affinity of the elicited repertoire, supporting more efficient LCMV clearance in WT mice than IL4I1-deficient mice. Conversely, IL4I1 restrains the differentiation of CD8 T-cells into long-lived memory precursors and favors the memory response to the most immunodominant peptides. IL4I1 expression does not affect the phenotype or antigen-presenting functions of dendritic cells (DCs), but directly reduces the stability of T-DC immune synapses in vitro, thus dampening T-cell activation. Overall, our results support a model in which IL4I1 increases the threshold of T-cell activation, indirectly promoting the priming of high-affinity clones while limiting memory T-cell differentiation.

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Chimeric Yellow Fever/Dengue Virus as a Candidate Dengue Vaccine: Quantitation of the Dengue Virus-Specific CD8 T-Cell Response

Journal of Virology ◽

10.1128/jvi.74.17.8094-8101.2000 ◽

2000 ◽

Vol 74 (17) ◽

pp. 8094-8101 ◽

Cited By ~ 77

Author(s):

Robbert G. van der Most ◽

Kaja Murali-Krishna ◽

Rafi Ahmed ◽

James H. Strauss

Keyword(s):

T Cells ◽

T Cell ◽

Dengue Virus ◽

Yellow Fever ◽

Cd8 T Cells ◽

Cell Response ◽

Protective Efficacy ◽

Cd8 T Cell ◽

T Cell Response ◽

E Proteins

ABSTRACT We have constructed a chimeric yellow fever/dengue (YF/DEN) virus, which expresses the premembrane (prM) and envelope (E) genes from DEN type 2 (DEN-2) virus in a YF virus (YFV-17D) genetic background. Immunization of BALB/c mice with this chimeric virus induced a CD8 T-cell response specific for the DEN-2 virus prM and E proteins. This response protected YF/DEN virus-immunized mice against lethal dengue encephalitis. Control mice immunized with the parental YFV-17D were not protected against DEN-2 virus challenge, indicating that protection was mediated by the DEN-2 virus prM- and E-specific immune responses. YF/DEN vaccine-primed CD8 T cells expanded and were efficiently recruited into the central nervous systems of DEN-2 virus challenged mice. At 5 days after challenge, 3 to 4% of CD8 T cells in the spleen were specific for the prM and E proteins, and 34% of CD8 T cells in the central nervous system recognized these proteins. Depletion of either CD4 or CD8 T cells, or both, strongly reduced the protective efficacy of the YF/DEN virus, stressing the key role of the antiviral T-cell response.

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A Critical Role for Cd40–Cd40 Ligand Interactions in Amplification of the Mucosal Cd8 T Cell Response

Journal of Experimental Medicine ◽

10.1084/jem.190.9.1275 ◽

1999 ◽

Vol 190 (9) ◽

pp. 1275-1284 ◽

Cited By ~ 62

Author(s):

Leo Lefrançois ◽

Sara Olson ◽

David Masopust

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Adoptive Transfer ◽

Cell Activation ◽

Cd8 T Cell ◽

Cd40 Ligand ◽

Interleukin 12 ◽

Cd8 Cells

The role of CD40 ligand (CD40L) in CD8 T cell activation was assessed by tracking antigen-specific T cells in vivo using both adoptive transfer of T cell receptor transgenic T cells and major histocompatibility complex (MHC) class I tetramers. Soluble antigen immunization induced entry of CD8 cells into the intestinal mucosa and cytotoxic T lymphocyte (CTL) differentiation, whereas CD8 cells in secondary lymphoid tissue proliferated but were not cytolytic. Immunization concurrent with CD40L blockade or in the absence of CD40 demonstrated that accumulation of CD8 T cells in the mucosa was CD40L dependent. Furthermore, activation was mediated through CD40L expressed by the CD8 cells, since inhibition by anti-CD40L monoclonal antibodies occurred after adoptive transfer to CD40L-deficient mice. However, mucosal CD8 T cells in normal and CD40−/− mice were equivalent killers, indicating that CD40L was not required for CTL differentiation. Appearance of virus-specific mucosal, but not splenic, CD8 cells also relied heavily on CD40–CD40L interactions. The mucosal CTL response of transferred CD8 T cells was MHC class II and interleukin 12 independent. The results established a novel pathway of direct CD40L-mediated CD8 T cell activation.

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T Cell Recognition of HCMV: Pan-Genome Analysis of Immunogenic Open-Reading Frames.

Blood ◽

10.1182/blood.v104.11.606.606 ◽

2004 ◽

Vol 104 (11) ◽

pp. 606-606 ◽

Cited By ~ 1

Author(s):

Louis J. Picker ◽

Andrew W. Sylwester ◽

Bridget L. Mitchell ◽

Cara Taormina ◽

Christian Pelte ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cell Response ◽

Cd8 T Cell ◽

Cross Reactivity ◽

T Cell Response ◽

Cd4 T Cell ◽

Cell Responses

Abstract Human Cytomegalovirus (HCMV) is among the largest and most complex of known viruses with 150–200nm virions enclosing a double stranded 230kb DNA genome capable of coding for >200 proteins. HCMV infection is life-long, and for the vast majority of immune competent individuals clinically benign. Disease occurs almost exclusively in the setting of immune deficiency, suggesting that the stable host-parasite relationship that characterizes these infections is the result of an evolutionarily “negotiated” balance between viral mechanisms of pathogenesis and the host immune response. In keeping with, and perhaps because of this balance, the human CD4+ T cell response to whole HCMV viral lysates is enormous, with median peripheral blood frequencies of HCMV-specific cells ~5–10 fold higher than for analogous preparations of other common viruses. Although certain HCMV ORFs have been identified as targets of either the CD4+ or CD8+ T cell response, the specificities comprising the CD4+ T cell response, and both the total frequencies and component parts of the CD8+ T cell response are unknown. Here, we used cytokine flow cytometry and ~14,000 overlapping 15mer peptides comprising all 213 HCMV ORFs encoding proteins >100 amino acids in length to precisely define the total CD4+ and CD8+ HCMV-specific T cell responses and the HCMV ORFs responsible for these responses in 33 HCMV-seropositive, HLA-disparate donors. An additional 9 HCMV seronegative donors were similarly examined to define the extent to which non-HCMV responses cross-react with HCMV-encoded epitopes. We found that when totaled, the median frequencies of HCMV-specific CD4+ and CD8+ T cells in the peripheral blood of the seropositive subjects were 4.0% and 4.5% for the total CD4+ or CD8+ T cell populations, respectively (which corresponds to 9.1% and 10.5% of the memory populations, respectively). The HCMV-specific CD4+ and CD8+ T cell responses included a median 12 and 7 different ORFs, respectively, and all told, 73 HCMV ORFs were identified as targets for both CD4+ and CD8+ T cells, 26 ORFs as targets for CD8+ T cells alone, and 43 ORFS as targets for CD4+ T cells alone. UL55, UL83, UL86, UL99, and UL122 were the HCMV ORFs most commonly recognized by CD4+ T cells; UL123, UL83, UL48, UL122 and UL28 were the HCMV ORFs most commonly recognized by CD8+ T cells. The relationship between immunogenicity and 1) HLA haplotype and 2) ORF expression and function will be discussed. HCMV-seronegative individuals were non-reactive with the vast majority of HCMV peptides. Only 7 potentially cross-reactive responses were identified (all by CD8+ T cells) to 3 ORFs (US32, US29 and UL116) out of a total of almost 4,000 potential responses, suggesting fortuitous cross-reactivity with HCMV epitopes is uncommon. These data provide the first glimpse of the total human T cell response to a complex infectious agent, and will provide insight into the rules governing immunodominance and cross-reactivity in complex viral infections of humans.

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