Molecular characterization of HCMV‐specific immune responses: Parallels between CD8⁺ T cells, CD4⁺ T cells, and NK cells

Abstract

CD8+ T cells are important for immunity against human cytomegalovirus (HCMV). The HCMV-specific CD8 IntroductionUpon viral infection the immune system engages lymphocytes such as NK cells, CD4 + and CD8 + T cells to eliminate the virus. CD4+ and CD8 + T cells recognize viral peptides presented by MHC class II (MHC-II) and MHC class I (MHC-I) molecules respectively. CD8 + T cells specific for the infecting pathogen first undergo massive expansion before they differentiate into cytotoxic cells capable of producing high levels of effector molecules such as IL-2, IFN-γ, TNF-α, perforin and granzyme B [1, 2]. Naïve CD4 + T cells alsoCorrespondence: Dr. Klaas P. J. M. van Gisbergen e-mail: k.vangisbergen@sanquin.nl expand and develop an effector (Th1) phenotype capable of secreting copious amounts of IFN-γ, IL-2 and TNF-α to assist CD8 + T-cell and B-cell responses [3]. To avoid T-cell detection and lysis of the infected cells, viruses of the Herpesviridae family including human cytomegalovirus (HCMV) have evolved mechanisms to downregulate MHC-I molecules on infected cells [4,5]. In turn, NK cells can detect downregulation of MHC expression and produce inflammatory cytokines such as IFN-γ, TNF-α, and cytotoxic granules containing effector molecules, such as perforin and the serine protease granzyme B, to eliminate infected cells [6,7]. HCMV is a member of the Herpesviridae family of doublestranded DNA viruses and has coevolved with humans for millions of years [8]. HCMV has a broad tropism for a wide range of tissues including endothelium, fibroblasts, smooth muscle, and C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2434 Felipe A. Vieira Braga et al. Eur. J. Immunol. 2015. 45: 2433-2445 hematopoietic cells. HCMV is a prevalent human pathogen, with 40-70% of the western population being seropositive for HCMV [9]. HCMV induces persistent infection, which can be divided into acute and latent phases, and which are respectively characterized by active replication and quiescence of the virus [10]. The majority of HCMV-infected individuals do not develop any symptoms, but immunocompromised individuals, such as transplant recipients and HIV + patients, are a risk group for HCMV infection and can present with symptoms such as vascular complications [8].In order to follow T-cell responses in humans, we and others have made extensive use of instances of primary HCMV infection of transplant patients, which occurs when an HCMV − recipient receives an organ transplant from an HCMV + donor. Using this system, the data show that the initial early T-cell response against HCMV peaks on average 7 days after the first detection of circulating CMV-DNA. The T-cell response is initially dominated by CD4 + T cells that have a T-helper 1 type cytokine signature, with high production of the cytokines IFN-γ and TNF-α, but not of the classical T-helper 2 cytokine . A few days after the initial CD4 + T-cell response, HCMV-specific CD8 + T cells with high cytotoxic potential can be detected in blood. Remarkably, after th...

Age and gender leucocytes variances and references values generated using the standardized ONE‐Study protocol

“…As illustrated in Figure , we also observed a considerable number of individuals with a high number of CD4 + CD57 + and CD4 + CD27 − T cells that could not be ascribed to aging alone, in contrast to CD8 + T cells where only a proportion (<30%) of healthy individuals display a steady increase in their proportions during aging. The accumulation of differentiated CD4 + T cells has been observed previously and may also result from latent viral infections such as described for their CD8 + counterpart , but may also be caused by Th2 driven responses in unreported allergies or other subclinical conditions, which was not examined among our participants.…”

Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection

“…Typically, exhausted T cells fail to control viral infection as they have effector defects (Wherry, 2011) including loss of proliferative potential, decreased cytotoxicity, impaired ability to secrete cytokines (Frebel et al, 2010; Wherry and Kurachi, 2015), and sustained high expression of several inhibitory receptors (e.g., PD1, KLRG1, and CD57) (Blackburn et al, 2009). Although HCMV-specific CD8 + T cells also have low proliferative capacity and express senescence markers, such as KLRG1 and CD57 (Vieira Braga et al, 2015), they are not exhausted as they are still highly cytotoxic and produce Th1 cytokines in response to sporadic viral re-activation (Klenerman and Oxenius, 2016). In addition, molecular profiling of HCMV-specific CD8 + T cells has demonstrated that PD-1, an inhibitory receptor associated with T cell dysfunction, is expressed at very low levels in healthy individuals (Vieira Braga et al, 2015).…”

“…Although HCMV-specific CD8 + T cells also have low proliferative capacity and express senescence markers, such as KLRG1 and CD57 (Vieira Braga et al, 2015), they are not exhausted as they are still highly cytotoxic and produce Th1 cytokines in response to sporadic viral re-activation (Klenerman and Oxenius, 2016). In addition, molecular profiling of HCMV-specific CD8 + T cells has demonstrated that PD-1, an inhibitory receptor associated with T cell dysfunction, is expressed at very low levels in healthy individuals (Vieira Braga et al, 2015). Therefore, persistent HCMV infection does not induce massive exhaustion of the T cell repertoire in most immunocompetent individuals.…”

Enhancement of cytokine‐driven NK cell IFN‐γ production after vaccination of HCMV infected Africans

“…However, NK cells can also contribute as effector cells to adaptive immune responses by mediating antigen-specific antibody-dependent cellular cytotoxicity (ADCC) [2,3] and producing IFN-γ in response to interleukin-2 (IL-2) secreted by antigen-specific CD4 + T cells [2,[4][5][6][7]. Moreover, it is recognized that NK cells undergo intrinsic transformation as a result of infection or inflammation [3,[8][9][10][11].…”