Acquisition of direct antiviral effector functions by CMV-specific CD4 T lymphocytes with cellular maturation

Immunology Laboratory, Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 01/2007; 203(13):2865-77. DOI: 10.1084/jem.20052246
Source: PubMed


The role of CD4+ T cells in the control of persistent viral infections beyond the provision of cognate help remains unclear. We used polychromatic flow cytometry to evaluate the production of the cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-2, the chemokine macrophage inflammatory protein (MIP)-1beta, and surface mobilization of the degranulation marker CD107a by CD4+ T cells in response to stimulation with cytomegalovirus (CMV)-specific major histocompatibility complex class II peptide epitopes. Surface expression of CD45RO, CD27, and CD57 on responding cells was used to classify CD4+ T cell maturation. The functional profile of virus-specific CD4+ T cells in chronic CMV infection was unique compared with that observed in other viral infections. Salient features of this profile were: (a) the simultaneous production of MIP-1beta, TNF-alpha, and IFN-gamma in the absence of IL-2; and (b) direct cytolytic activity associated with surface mobilization of CD107a and intracellular expression of perforin and granzymes. This polyfunctional profile was associated with a terminally differentiated phenotype that was not characterized by a distinct clonotypic composition. Thus, mature CMV-specific CD4+ T cells exhibit distinct functional properties reminiscent of antiviral CD8+ T lymphocytes.

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Available from: Joseph P Casazza
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    • "These cytolysins are released early after CD8+ T-cell activation into the immunological synapse, and this process of degranulation is MHC class I-restricted and antigen-specific [23]. Although it has been shown that CD4+ T cells lyse target cells via Fas–FasL interactions [24] [25], GE-mediated CD4+ T-cell cytotoxicity has also been demonstrated in human infections with human cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein–Barr virus (EBV), influenza virus and HIV [26] [27] [28] [29] [30] [31]. Having said that CTLs have a key function in host immune surveillance, they reportedly play a vital role in host defense against HIV-1, by impeding viral replication through both cytolytic and non-cytolytic pathways [32] [33] [34]. "
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    • "MHC class II restricted CD4 effectors with cytolytic potential have been described since the late 1970s [3] and while early reports confined this activity to in vitro stimulated CD4 effectors [4]–[6], recent data underscores this cell type as an important mediator of viral clearance (reviewed in [7]–[9]). Cytolytic CD4 T cells (CD4 CTL) have been identified in humans with chronic infections such as Epstein-Barr Virus [10], cytomegalovirus [11] and Human Immunodeficiency Virus [12], suggesting prolonged exposure to antigen induces a terminally differentiated effector capable of cytotoxic activity. CD4 CTL have also been described during acute viral infections such as influenza [13], [14], LCMV [15], and ectromelia virus [16]. "
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