In vitroPeptide Immunization of Target Tax Protein Human T-Cell Leukemia Virus Type 1–Specific CD4+ Helper T Lymphocytes

Abstract

Purpose: Adult T-cell leukemia/lymphoma induced by human T-cell leukemia virus type 1 (HTLV-1) is usually a fatal lymphoproliferative malignant disease. HTLV-1 Tax protein plays a critical role in HTLV-1-associated leukemogenesis and is an attractive target for vaccine development. Although HTLV-1Tax is the most dominant antigen for HTLV-1-specific CD8 + CTLs in HTLV-1-infected individuals, few epitopes recognized by CD4 + helper T lymphocytes in HTLV-1Tax protein have been described. The aim of the present study was to study T-helper-cell responses to HTLV-1 Tax and to identify naturally processed MHC class II^restricted epitopes that could be used for vaccine development. Experimental Design: An MHC class II binding peptide algorithm was used to predict potential T-helper cell epitope peptides from HTLV-1 Tax. We assessed the ability of the corresponding peptides to elicit helper T-cell responses by in vitro vaccination of purified CD4 + T lymphocytes. Results: Peptides Tax 191-205 and Tax 305-319 were effective in inducing T-helper-cell responses. Although Tax [191][192][193][194][195][196][197][198][199][200][201][202][203][204][205] was restricted by the HLA-DR1 and DR9 alleles, responses to Tax [305][306][307][308][309][310][311][312][313][314][315][316][317][318][319] were restricted by either DR15 or DQ9. Both these epitopes were found to be naturally processed by HTLV-1 + T-cell lymphoma cells and by autologous antigen-presenting cells that were pulsed with HTLV-1Tax + tumor lysates. Notably, the two newly identified helper T-cell epitopes are found to lie proximal to known CTL epitopes, which will facilitate the development of prophylactic peptide^based vaccine capable of inducing simultaneous CTL and T-helper responses. Conclusion: Our data suggest that HTLV-1 Tax protein could serve as tumor-associated antigen for CD4 + helper T cells and that the present epitopes might be used for T-cell-based immunotherapy against tumors expressing HTLV-1.

Induction of EBV–Latent Membrane Protein 1–Specific MHC Class II–Restricted T-Cell Responses against Natural Killer Lymphoma Cells

“…Here, we show for the first time that the LMP1 antigen is processed and presented to CD4 HTLs in the context of HLA class II molecules through the endogenous (direct presentation by transformed cells) or the exogenous (antigens captured and processed by conventional APC) pathways. In our studies, three peptides (LMP1 [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] , LMP1 102-116 , and LMP1 159-175 ), which did not correspond to those described by Leen and Depil (24,25) were predicted to potentially function as promiscuous HTL epitopes. Out of the three peptides, only one, LMP1 159-175 , proved to be effective at inducing HTL responses.…”

“…As with previous studies (22,(30)(31)(32)(33)(34)(35)(36), an MHC class II peptide binding predictive algorithm (29) was used to select candidate peptides from the LMP1 sequence that would bind to the products of three common human MHC class II alleles (HLA-DR1, HLA-DR4, and HLA-DR7). Three peptides, LMP1 [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] (ALLFWLYIVMSDWTG), LMP1 102-116 (GQALFLGIVLFIFGC), and LMP1 159-175 (YLQQNWWT-LLVDLLWLL) were identified as potentially binding the three MHC class II alleles (data not presented), suggesting these could function as promiscuous HTL epitopes. In past studies, we have observed that peptide sequences predicted to bind to HLA-DR1, HLA-DR4, and HLA-DR7 have elicited HTL responses restricted by additional MHC class II alleles, such as DR9, DR13, DR15, or DR53 (22,30,32,(34)(35)(36).…”

“…On the other hand, there is a report of significant amount of antibodies to LMP1 in sera of patients with EBV-associated NPC (46), suggesting that the immunogenic potential of this antigen may vary depending on the type of disease. Another potential explanation to our inability to generate HTL responses to peptides LMP1 [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] and LMP1 102-116 is that these peptides may not bind with sufficient strength to the MHC class II alleles expressed by the blood donors used in the present study. Although we cannot exclude the possibility that LMP1 [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] and LMP1 102-116 may function as HTL epitopes, our studies show that LMP1 159-175 was capable of stimulating HTL responses in several individuals in the context of at least three MHC class II alleles and that the resulting HTLs were effective in recognizing naturally processed antigen.…”

Recognition of Prostate and Melanoma Tumor Cells by Six-Transmembrane Epithelial Antigen of Prostate–Specific Helper T Lymphocytes in a Human Leukocyte Antigen Class II–Restricted Manner

“…14). The in silico prediction system that was used is based on the algorithm tables described by Southwood et al (14) and has been useful in identifying HTL epitopes from numerous TAAs (15,(17)(18)(19)(20)(21)(22)(23)(24)(25). In many instances, the predicted peptides were able to elicit HTL responses restricted by MHC class II alleles other than HLA-DR1, HLA-DR4, and HLA-DR7 (e.g., HLA-DR9, HLA-DR13, HLA-DR15, HLA-DR51, HLA-DR52, and HLA-DR53), indicating that this prediction system extends beyond the original three MHC alleles.…”

Potential Contribution of a Novel Tax Epitope–Specific CD4+ T Cells to Graft-versus-Tax Effect in Adult T Cell Leukemia Patients after Allogeneic Hematopoietic Stem Cell Transplantation

“…However, there are only a few reports of HTLV-1-specific Th cell responses (20)(21)(22)(23), presumably because of their susceptibility to HTLV-1 infection in vivo and in vitro (24). Preferential HTLV-1 infection in HTLV-1-specific CD4 + T cells could be one of the reasons for immune suppression in ATL patients.…”