Tissue maintenance of CMV-specific inflationary memory T cells by IL-15

20Cytomegalovirus (CMV) is a ubiquitous β-herpesvirus that establishes life-long latent infection 21 in a high percentage of the population worldwide. CMV induces the strongest and most durable 22 CD8 + T cell response known in human clinical medicine. Due to its unique properties, the virus 23 represents a promising candidate vaccine vector for the induction of persistent cellular 24 immunity. To take advantage of this, we constructed a recombinant murine CMV (MCMV) 48 but only if we administered it through the nose, to activate killer T cells that will persist in the 49 lungs close to the airways. Therefore, our data show that the subset of lung-resident killer T 50 cells is sufficient to protect against influenza. 3 51 Introduction 52 Respiratory infections caused by influenza viruses usually are associated with mild-to-53 moderate disease symptoms but are linked with high morbidity and mortality in susceptible 54 populations like the elderly, young children, patients with co-morbidities and 55 immunocompromised patients. Influenza virus causes seasonal epidemics, with typically 3 to 56 5 million cases of severe illness worldwide, according to WHO reports [1], and influenza type 57 A viruses (IAV) cause the more severe disease form. Vaccines against influenza are based on 58 the induction of adaptive immunity that targets the projected yearly epidemics. While most 59 vaccines are based on inactivated IAV formulations inducing anti-IAV IgG responses, live 60 attenuated influenza vaccines (LAIV) are also used as formulations for i.n. administration. This 61 is based on the assumption that the induction of local immunity may provide superior immune 62 protection [2, 3]. However, it remains unclear whether this protection depends on local IgA 63 responses, on cytotoxic T cell responses, or on their combined antiviral activity. Of note, 64 functional T cell responses were shown to substantially contribute to antiviral IAV immunity [4-65 6]. In particular, cytotoxic influenza-specific CD8 + T lymphocytes (CTLs) promote viral 66 clearance indirectly by secretion of pro-inflammatory cytokines such as IFNγ [7] and directly 67 by perforin/Fas-mediated killing of infected epithelial cells in the bronchoalveolar space [8]. 68 However, it remained unclear if T cell responses alone may control IAV, or if Ig responses were 69 the crucial contributor to LAIV-mediated immune protection. We considered that this question 70 could be addressed by developing a vaccine formulation that optimizes T cell responses 71 against IAV, while excluding the humoral ones. 72 CMV infection induces sustained functional T cell responses that are stronger in the long-term 73 than the immune response to any other infectious pathogen [9]. Experiments in the mouse 74 model have shown that defined CMV epitope-specific CD8 + T cells accumulate in tissues and 75 blood and are maintained at stable high levels during mouse CMV (MCMV) latency [10]. This 76 phenomenon was termed ''Memory Inflation'' [11]. While some MCMV derived peptides, as the 77 ones de...

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“…CD8T RM are found in the salivary glands of MCMV-infected animals [29], but not in their lungs [30]. We showed that i.n.…”

Section: Introductionmentioning

confidence: 98%

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

Zheng

Oduro

Boehme

et al. 2018

Preprint

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“…Furthermore, while inflationary cells are more abundant in lungs than in lymph nodes, the inflationary T-cells expressing the proliferation marker Ki67 were shown to be more abundant in lymph nodes than in lungs (20), suggesting that cycling central-memory T-cells may continuously feed the large pool of inflationary cells in the tissues. On the other hand, blocking lymphocyte egress from lymph nodes does not impair the blood and splenic proliferation of inflationary T-cells (21), and our recent data indicate that inflationary EM cells proliferate by IL-15 driven, homeostatic, proliferation (22). Taken together, these data suggest that the inflationary pool is maintained by systemic hematogenous proliferation of T-cells, rather than by the proliferation of central-memory T-cells in lymph nodes.…”

Section: Introductionmentioning

confidence: 87%

Off-target effects of Cre recombinase reveal limits of adoptive T cell transfers and persistent proliferation of effector CD8 T-cells

Borkner

Drabig

Zheng

et al. 2018

Preprint

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20Effector-memory T-cells (TEM) are assumed to be short-lived cells that poorly proliferate upon 21 antigenic restimulation, thus depending on central-memory T-cells (TCM) to replenish their numbers 22 during homeostasis, largely depending on adoptive transfer evidence. Here we analyzed T cells in 23 their natural environment and observed robust long-term in vivo cycling within the TEM subset that 24 was stronger than the one in the TCM subset. Murine Cytomegalovirus (MCMV) induces inflationary 25 TEM responses that remain high during latency. We analyzed Ki67 expression during acute and latent 26 MCMV infection and found Ki67 hi Bcl2 lo TEM in latently infected mice, arguing for antigen-driven TEM 27 proliferation. TEM acquired deuterium more rapidly than TCM in an in vivo labeling experiment, and 28 were replenished more rapidly than TCM after memory depletion, suggesting that TEM cycle faster 29 than TCM. We depleted selectively the proliferating T-cells by Cre-overinduction, which resulted in a 30 selective loss of Ki67 hi Bcl2 lo effector T-cells, and an increase in the death of TEM in the spleen, while 31 it hardly affected the TCM subset, arguing for robust proliferation of TEM in the spleen. On the other 32 hand, TEM homing to the spleen upon adoptive transfer was substantially poorer than TCM, 33 explaining the previously reported expansions of TCM, but not TEM, upon transfer. In conclusion, our 34 data suggest that memory inflation is maintained by proliferation of antigen-specific TEM, rather 35 than by continued expansion and differentiation of TCM. 36 37 Running title: TEM proliferation during MCMV latency 3 38 Author Summary 39 The naïve T cell population consists of T cells that have the potential to recognize millions of 40 different pathogens. Upon infection, naïve T cells that recognize the pathogen expand, and 41 differentiate into effector T cells that eliminate infected cells. Once the infection is contained, the T 42 cell pool contracts and only a small population of central memory T cells remains that can expand 43 quickly upon re-infection. Cytomegaloviruses cause persistent infections that are not cleared from 44 the organism after the initial immune response. In infected individuals a pool of CMV-specific 45 effector memory T cells dominates the immune system in a phenomenon called memory inflation. 46 Previous research using the transfer of central memory or effector memory T cells from CMV-47 infected mice into mice with a matching infection, showed expansion of central memory T cells but 48 not effector memory T cells. Here we show that effector memory T cells have a reduced capacity to 49 home into lymphoid organs, where T cell activation takes place, compared to central memory T cells. 50 Using methods that do not interfere with T cell differentiation and homing, we show that effector 51 memory T cells are proliferating during the persistent phase of CMV infection, significantly 52 contributing to the upkeep of the inflationary population. 53 126 Ki67 hi CD8 T-cells was substantiall...

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“…Thus, current MI definition integrates these findings in three cardinal characteristics [7] (1) Restricted contraction after priming, with a durable memory pool, (2) Dominant and sustained effector phenotype and (3) No signs of exhaustion. Adoptive transfer experiments in mouse models showed that MCMV-specific TEM have a half-life of 45 days to 12 week [96,120] and are differentiated from TCM during viral reactivation with no need of new thymic emigrants [121]. The localization where the presumed reactivation events and TCM activation takes place is still a matter of debate.…”

Section: Cellular Response-t Cellsmentioning

confidence: 99%

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

2019

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Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.Vaccines 2019, 7, 152 2 of 28 CMV-based vaccines, the large pool of functional antigen-specific T cells in the periphery and the possibility to modify CMV genomes due to improvements in viral genetics [11] draw a strong interest to CMV as a vaccine vector [12,13] (Table 1). The inflationary response appears linked to immune protection [14,15] and has been proposed as a target for immunization induction [16]. Vaccines 2019, 7, 152 3 of 28 Full-length HPV16 E6 and E7 Antigen fused to the C-terminus of ie2 Transient limitation of tumour cell growth MCMV IE2E7 [14] MHC-I restricted HPV16 E7 49-57 epitope Epitope fused to the C-terminus of ie2 No tumour cell growth upon challenge MCMV-M79-FKBP-E7 [36] MCMV Smith Strain with FKBP-mediated destabilization of the essential M79 gene Vaccines 2019, 7, 152 5 of 28Besides the exceptional induction of adaptive immune response in humans [2,37], CMV possesses assets that conveniently address weaknesses common to other vector candidates. The cloning of CMV genomes as bacterial artificial chromosomes in Escherichia coli [38] has allowed genetic engineering approaches to effectively express multiple exogenous immunogens or modify large genome portions [39,40]. Furthermore, CMV is known to superinfect hosts with a history of prior exposure to the virus [41] due to its immune evasive properties that protect the virus from recognition by primed T-cells [42] and CMV vectors induce protective immunity in experimentally vaccinated animals with documented prior exposure to 36]. Therefore, CMV vector candidates would avoid immune interference as described for AdV. CMV is a pathogenic organism in immunodeficient populations [43] or in congenitally infected children. Therefore, it is imperative for any HCMV vaccine vector to be attenuated. The generation of replication deficient CMVs that maintain their immunogenicity [36,44] and the modification of genome portions that contain evasions genes [45], as well as the insertion of activating ligands to increase immune control of CMV [46][47][48] are strategies that will be described in this review. Inter...

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Tissue maintenance of CMV-specific inflationary memory T cells by IL-15

Cited by 46 publications

References 78 publications

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

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

Off-target effects of Cre recombinase reveal limits of adoptive T cell transfers and persistent proliferation of effector CD8 T-cells

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

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