Linked Foreign T-Cell Help Activates Self-Reactive CTL and Inhibits Tumor Growth

Abstract

Transgenic mice expressing membrane-bound OVA under the rat insulin promoter, RIP-mOVA, has previously been suggested to display deletional tolerance toward the dominant CTL epitope, SIINFEKL, and provide an elegant model system to test the hypothesis that the lack of T cell help contributes to the tolerance. To understand how the CD8 tolerance is maintained in these mice, a set of neo-self-Ags, OVA, modified to contain a foreign Th peptide, were constructed and tested for their ability to induce CTL responses in RIP-mOVA mice. Immunization with these Th peptide-modified OVA molecules and not with the wild-type OVA induced self-reactive CTLs recognizing dominant CTL peptide, SIINFEKL. Importantly, immunization with the modified OVA constructs also prevented the growth of OVA-expressing tumors in transgenic mice. Since endogenous OVA Th peptides did not contribute toward breaking self CTL tolerance, these results also highlighted a very robust CD4 T cell tolerance toward OVA in RIP-mOVA mice that has not been previously described. These results therefore provide direct evidence that it is the tolerance in the CD4 Th cell compartment that helps maintain the CTL tolerance against self-Ag in these mice. Since the CTL tolerance can be broken or bypassed by foreign Th peptides inserted into a self Ag, potential of using this approach in generating effective therapeutic cancer vaccines is discussed.

Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

“…This suggestion is consistent with previously reported synergy between anti-OX40 and anti-4-1BB, which was not abrogated by CD4 1 T-cell depletion [39]. In addition, in RIPmOVA mice used in this study, central tolerance to CD4 1 T-cell epitopes is reported to be complete [40], suggesting that the CD8 1 T-cell responses we have seen are not dependent on CD4 1 T-cell help. However, such observations do not exclude other mechanisms, including the involvement of other cell types, such as DC or Treg (below).…”

“…Although, given the role of OX40 in CD4 1 T-cell function, this would seem a likely possibility, previously reported synergy between anti-OX40 and anti-4-1BB has not been abrogated by CD4 1 T-cell depletion [39]. In addition, in RIPmOVA mice, central tolerance to CD4 1 T-cell epitopes is reported to be complete [40], suggesting that the CD8 1 T-cell responses seen in this model were not dependent on CD4 1 T-cell help.…”

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

“…First, the presence of CD4 help has been shown to inhibit induction of peripheral tolerance in CD8 1 T cells specific for self-antigens and to promote effector differentiation of CD8 1 T cells and subsequent autoimmune destruction [9,11]. Second, immunization with antigen linked to heterologous helper epitopes can restore effector function in cognate CD8 1 T cells, presumably by reversing unresponsiveness in vivo [10,37]. Additionally, restimulation of memory CD4 1 T cells in vivo promotes effector differentiation of antigenstimulated naïve CD8 1 T cells [38].…”

Potent CTL Induction by a Whole Cell Pertussis Vaccine in Anti‐Tumor Peptide Immunotherapy

“…Immunity against foreign antigens is generally free from the constraint of self-tolerance, and thus is strong. A strong helper activity against foreign antigen has been shown to be effective for breaking the tolerance of CTLs specific for selftumor antigens (56). On the other hand, there are also reports that CD4 T cells are necessary for the infiltration of tumor specific CD8 T cells into solid tumors (27).…”