Cognate CD4 T-Cell Licensing of Dendritic Cells Heralds Anti-Cytomegalovirus CD8 T-Cell Immunity after Human Allogeneic Umbilical Cord Blood Transplantation

Abstract

Reactivation of human cytomegalovirus (CMV) is hazardous to patients undergoing allogeneic cord blood transplantation (CBT), T-cell-mediated immunity and fight off viral reactivation in CBT patients. IMPORTANCE Survival rates after stem cell transplantation are lowered by 25% when patients undergo reactivation of cytomegalovirus (CMV) that they harbor. Immune protection against CMV is mostly executed by white blood cells called killer T cells. We here show that for generation of optimally protective killer T-cell responses that respond to CMV, the early elicitation of help from a second branch of CMV-directed T cells, called helper T cells, is required.C ytomegalovirus (CMV)-seropositive patients who are immunocompromised are at increased risk for developing potentially life-threatening CMV reactivation. Especially after allogeneic cord blood (CB) transplantation (CBT), the first weeks of immune reconstitution are hazardous for developing CMV reactivation, which is associated with decreased survival rates (1, 2). Antiviral treatment can reduce CMV viremia, but effective viral control requires induction of CMV-directed immunity by T lymphocytes. In particular, CD8 ϩ cytotoxic T lymphocytes (CTLs) fulfill a predominant role in protection against CMV disease (2-4). Therefore, strategies that increase early CMV-specific adaptive immune responses after transplantation are currently being explored, which could ultimately help to establish full clearance of, and long-term immunological memory against, CMV. In the human setting, cell-based therapy is being explored, geared toward dendritic cell (DC)-mediated activation of CTLs (5, 6). The elicitation of antigen-specific CTL immunity was in mouse models shown to require cognate CD4 ϩ T-cell licensing (7-10). Furthermore, priming of naive CD8 ϩ T cells requires both the CD4 ϩ T-helper cells and CD8 ϩ T cells to recognize antigen on the same antigen-presenting cell (5,11,12). Such CD4 ϩ T-cell help can involve CD40 ligand (CD40L) binding to CD40 on DCs (9,13,14). For humans, a requirement for CD4 CMV-specific CD4ϩ T-cell clones are present in the healthy population, suggesting a role for antigen-specific CD4 ϩ T cells in immunity against CMV, as 50 to 80% of adults experience CMV infection in their lifetime (6,15). Moreover, effective control of CMV infection was attained in patients when CMV-specific T cells, of which 77% were CD4 ϩ T cells, were infused (16). Further, human DCs loaded with both HLA class I and II/peptide complexes were more effective at generating antigen-specific CTL responses than were those loaded with solely major histocompatibility complex (MHC) class I/peptide complexes (17). In a different setting, not only the absence of antigen-specific CTLs but also the absence of specific CD4 ϩ T-helper cells resulted in higher

CMV drives the expansion of highly functional memory T cells expressing NK‐cell receptors in renal transplant recipients

“…In one study of solid organ transplantation, presence of only CMV‐specific CD8 + T cells could not control CMV infection, but reconstitution of CD4 + T cells after antiviral therapy was protective . Antigen‐specific CD4 + T cells license APCs that cross‐present the same antigen to CD8 + T cells, which then become cytolytic effector cells . In bone marrow transplant recipients, CMV‐specific CD4 + T cells were needed to maintain a protective CMV‐specific CD8 + T cell pool .…”

Abatacept Inhibition of T Cell Priming in Mice by Induction of a Unique Transcriptional Profile That Reduces Their Ability to Activate Antigen‐Presenting Cells

“…Indeed, CD28 signaling has been reported to stabilize CD40L expression on T cells (55), which is important for DC conditioning. In contrast, T cells primed in the presence of abatacept have a reduced ability to produce effector cytokines, such as IFNg and IL-17, which have been reported to mediate DC licensing and activation (56,57). The hypothesis of reduced licensing of CD11c1 cells is also reinforced by the reduced expression of chemokines such as CXCL16 and CXCL9 by CD11c cells, which are induced by inflammatory cytokines such as IFNg and TNF, which are readily produced by T cells (34,58).…”

The Antitumor Efficacy of IL2/IL21-Cultured Polyfunctional Neu-Specific T Cells Is TNFα/IL17 Dependent

“…Investigations in both infectious disease and cancer have underscored the role of CD4 Th. Interferon-gamma secreting CD4+ T-cells have been shown to activate dendritic cells resulting in the generation of CMV specific CD8+ T-cells (42). In vitro studies demonstrate antigen specific CD4 are required to effectively stimulate functional CMV-specific cytotoxic T-cells.…”