Soluble Antigen and CD40 Triggering Are Sufficient to Induce Primary and Memory Cytotoxic T Cells

Abstract

The signals directing induction of tolerance rather than immunity are largely unknown. The CD8 T cell response to soluble Ags generally results in deletional tolerance following transient, costimulation-dependent activation. We demonstrated that CD40 signaling reversed the outcome of this response. Adoptive transfer of OVA-specific CD8 T cells followed by soluble OVA immunization resulted in induction of lytic activity and optimal clonal expansion only when CD40 was triggered via an agonistic mAb. Activation of CD8 T cells by CD40 signaling was indirect, because CD40 expression by host cells was required. CD40 signaling along with soluble Ag immunization also induced expansion of secondary lymphoid and intestinal mucosal endogenous OVA-specific CD8 T cells as detected by MHC tetramer reactivity. When CD40 activation was included, long-lived secondary lymphoid and mucosal memory CD8 cells were generated from adoptively transferred and endogenous CD8 T cells. Mucosal and peripheral CD8 memory cells exhibited constitutive Ag-specific lytic activity, with mucosal memory cells being 10-fold more lytic than splenic or lymph node memory cells. These results demonstrated that CD40 signaling during a response to a poorly immunogenic soluble Ag was necessary and sufficient for CTL and memory T cell induction.

CD40 Signaling Converts a Minimally Immunogenic Antigen into a Potent Vaccine Against the Intracellular Pathogen Listeria monocytogenes

“…However, a range of other cell types such as macrophages or endothelial cells may also be involved. A small proportion of T cells can express CD40 (25), although, in a similar system, it was shown that anti-CD40 mAb did not act directly on T cells (26).…”

CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

“…Engagement of CD40 by CD40L can induce activation and maturation of immature DCs, prevent their apoptosis, and "license" them to prime CD8 + T cell responses. In fact, previous studies showed that CD40 stimulation alone could substitute CD4 + T cells in generating CD8 + T cell responses [20][21][22][23]. Stimulation of CD40, mainly through agonistic anti-CD40 antibody, has been used experimentally to enhance immune responses elicited by antigens from bacteria, viruses, and tumors (see reference [24] for review).…”

T Cell Immunity to Lymphoma Following Treatment with Anti-CD40 Monoclonal Antibody

“…For example, CD40 ligation has been shown to promote CTL responses to peptide and protein Ags with known epitopes (12,13), and functioned therapeutically against tumors where the targets were not defined (16,18). It appears that in most situations these are Th1-skewed responses and that they occur without CD4 T cell help.…”

“…Results such as these support the view that CD40 stimulation promotes a pattern of cytokine production that skews toward a Th1-type immune response (11). Importantly, CD40 mAb and soluble CD40L are already showing evidence of clinical potential, being able to potentiate immune responses in a number of therapeutic settings, including T cell responses to peptides and proteins (12,13), infectious disease (14,15), and treating neoplastic disease in animals and patients (16 -19).…”