Induction of cytotoxic T‐cell response by optimal‐length peptides does not require CD4⁺ T‐cell help

Abstract

SUMMARYIn several experimental models, synthetic peptides were shown to activate efficiently cytotoxic Tlymphocyte (CTL) responses and therefore represent an attractive strategy to develop new vaccines. However, the mechanisms by which they induce CTL responses are not yet fully understood. Several studies using 15-16-mer peptides previously demonstrated that CD4helper T cells are required to induce optimal CTL responses with synthetic peptides. However, recently, it was suggested that shorter 8-12-mer peptides could have an increased in vivo immunogenicity. In the present study, we therefore investigated if such optimal-length peptides still require CD4T-cell help to activate CTL responses. To address this question, three synthetic peptides containing different viral CTL epitopes were injected into mice depleted of CD4 or CD8 T cells using specific monoclonal antibodies or into mice genetically deficient in those T-cell populations. Our results clearly established that activation of CTL responses by those short optimal peptides does not require CD4T-cell help and therefore suggested that high-density binding of peptides to major histocompatibility complex class I molecules on the surface of antigen-presenting cells is required for direct activation of CD8 T cells, independently of CD4 T-cell help.

mRNA-based cancer vaccine: prevention of B16 melanoma progression and metastasis by systemic injection of MART1 mRNA histidylated lipopolyplexes

“…CD4 þ T-helper cells play also a key role in the establishment of the CTL response. [47][48][49] MART1 mRNA lipopolyplexes also induced CD4 þ IFN-g-positive T cells. There are growing bodies of evidence showing that in humans one epitope of MART1 can be presented via MHC class II leading to a stimulation of CD4 þ T cells inducing a IFN-g secretion.…”

CD4+/CD25+ Regulatory Cells Inhibit Activation of Tumor-Primed CD4+ T Cells with IFN-γ-Dependent Antiangiogenic Activity, as well as Long-Lasting Tumor Immunity Elicited by Peptide Vaccination

“…CD4 ϩ Th cells play an important role on the induction of CTL (23,(31)(32)(33)(34). However, it has also been described that depletion of CD4 ϩ T cells may favor the induction of CTL responses (14,22,35), and enhance the therapeutic efficacy in tumor rejection (14,35) suggesting that CD4 ϩ T cells play a regulatory role.…”

“…Many studies, including our own, have described the role of CD4 ϩ T cells in providing help for the induction of CTLs (23,(31)(32)(33)(34)36). However, CD4 ϩ T cells can coordinate other antitumor effector pathways independent of CTLs (37).…”

A new era in anticancer peptide vaccines

“…14,15 In addition to those artificial polyepitope vaccines, naturally linked and usually overlapping CTL and T h epitopes also performed well as vaccines in preclinical mouse models. 16,17 Furthermore, naturally occurring, linked CTL and T h epitopes with improved immunogenicity are present in humans, such as human papillomavirus (HPV), 18,19 NY-ESO-1 (a cancer testis antigen), 20 and HER-2/neu. 21,22 One of the major mechanisms for the enhanced vaccine potency of long peptides is most likely that, unlike 8-mer to 10-mer CTL epitopes, these are not able to bind directly to MHC class I molecules, so their presentation to CTL precursors must follow processing by DCs.…”

“…The necessity of CD4-positive T-cell help to generate and sustain the MHC class I-restricted, CD8-positive T-cell responses has led to the use of MHC class II-restricted epitopes derived from the same protein 16,35 and also to universal, nonspecific MHC class II-restricted epitopes, such as pan-DR T h epitope (PADRE), in clinical vaccination trials that included patients with melanoma who were immunized with melanoma antigen 3 (MAGE-3) CTL peptides and patients with cervical carcinoma who were vaccinated with HPV16 E7 CTL peptides. 36,37 Although those studies demonstrated the capacity of PADRE to induce potent responses to PADRE itself, this did not increase CTL activity.…”