Novel peptide-based vaccines efficiently prime murine “help”-independent CD8+ T cell responses in the liver

Abstract

Vaccines for the prophylactic and/or therapeutic immunization against hepatotropic pathogens (e.g., hepatitis B and hepatitis C virus) should establish long-lasting, specific antiviral effector/memory CD8 ؉ T cell immunity in the liver. We describe a novel peptide-based vaccine in which antigenic major histocompatibility complex Class I-binding peptides are fused to a cationic (e.g., human immunodeficiency virus tat-derived) domain and complexed to immune-stimulating oligonucleotides. This vaccine formulation efficiently primes liverhoming, Class I-restricted CD8 ؉ effector/memory T cell responses. In different antigen systems, this formulation was more potent in priming liver-homing CD8 ؉ T cell responses than DNA-based vaccines delivering the same epitopes. CD8 ؉ T cell priming was independent of CD4 ؉ T cell "help" but submitted to regulatory control by CD25 ؉ CD4 ؉ T cells. The vaccine efficiently primed memory/effector CD8 ؉ T cells detectable in the liver for more than 3 months after a single injection. With increasing time after priming, the phenotype of these specific memory CD8 ؉ T cells shifted from an effector memory to a central memory type. The vaccine could override T cell tolerance in mice expressing the relevant antigen from a transgene in the liver. The CD8 ؉ T cell immunity in the liver primed by this peptide formulation could be boosted by challenge injections. In conclusion, we describe a simple and potent vaccine formulation that has the potential to generate or reconstitute specific CD8 ؉ T cell immunity to hepatotropic pathogens in the liver. (HEPATOLOGY 2004;40: 300 -309.)

IL-20 Receptor 2 Signaling Down-Regulates Antigen-Specific T Cell Responses

“…The regulation of Ag-specific CD8 responses is therefore of major therapeutic interest (41)(42)(43)(44). In summary, we could show that IL-20R2 regulates T cell activation directly and attenuates Ag-specific CD8 responses.…”

Local accumulation and activation of regulatory Foxp3+ CD4 TR cells accompanies the appearance of activated CD8 T cells in the liver

“…Mice were immunized intramuscularly with the hepatitis B surface antigen (HBsAg)‐ or S‐encoding pCI/S DNA vaccine (50 μg per mouse) or the antigenic/cationic S 190‐197 (S2) VWLSVIWM‐KKRRQRRR peptide (20 μg/mouse) complexed to oligodeoxynucleotide (ODN) 14. OT‐I RAG1 −/− mice were immunized intramuscularly with 0.5 μg/mouse OVA 257‐264 peptide mixed with 10 μg ODN.…”

“…OT‐I RAG1 −/− mice were immunized intramuscularly with 0.5 μg/mouse OVA 257‐264 peptide mixed with 10 μg ODN. K b /S2 tetramer + CD8 T cells and IFNγ + CD8 T cells (induced by a 4‐hour ex vivo specific peptide restimulation) were determined as described 14…”

Cytotoxic Effector Function of CD4-Independent, CD8+ T Cells Is Mediated by TNF-α/TNFR

“…We have previously reported that hepatocyte allografts initiate CD8-dependent rejection and in vivo allospecific cytotoxic effector function mediated by CD8 + T cells whose maturation is either CD4-dependent or CD4-independent (10, 11). While it is generally appreciated that CD8 + T cells require CD4 + T cell help for development of maximal effector function, CD8 + T cells can also be activated directly by antigen presenting cells without CD4 + T cell help when adjuvants or infectious agents are present (12–14). Although the contribution of CD4 + T cell help to CD8-mediated cytotoxic effector function is not clear, CD4 + T cells are known to contribute to CD8 + T cell expansion and, under some circumstances, facilitate trafficking to the site of inflammation (15, 16).…”