CD4 Help-Independent Induction of Cytotoxic CD8 Cells to Allogeneic P815 Tumor Cells Is Absolutely Dependent on Costimulation

Abstract

Mice made transgenic (Tg) for a rat anti-mouse CD4 Ab (GK mice) represent a novel CD4-deficient model. They not only lack canonical CD4 cells in the periphery, but also lack the residual aberrant Th cells that are found in CD4−/− mice and MHC class II−/− mice. To analyze the role of CD4 help and costimulation for CTL induction against alloantigens, we have assessed the surface and functional phenotype of CD8 cells in vivo (e.g., clearance of allogeneic P815 cells) and in vitro. In our CD4-deficient GK mice, CTL responses to allogeneic P815 cells were induced, albeit delayed, and were sufficient to eliminate P815 cells. Induction of CTL and elimination of allogeneic P815 cells were inhibited both in the presence and absence of CD4 cells by temporary CD40 ligand blockade. This indicated that direct interaction of CD40/CD40L between APCs and CD8 cells may be an accessory signal in CTL induction (as well as the indirect pathway via APC/CD4 interaction). Furthermore, whereas in CTLA4Ig single Tg mice P815 cells were rejected promptly, in the double Tg GK/CTLA4Ig mice CTL were not induced and allogeneic P815 cells were not rejected. These findings suggest that CD40/CD40L is involved in both CD4-dependent and CD4-independent pathways, and that B7/CD28 is pivotal in the CD4-independent pathway of CTL induction against allogeneic P815 cells.

Local recall responses in the stomach involving reduced regulation and expanded help mediate vaccine‐induced protection against Helicobacter pylori in mice

“…GK1.5 mice are transgenic for both heavy and light chains of the anti-CD4 GK1.5 mAb expressed under the CMV promoter [21] and as a result are deficient of CD4 1 cells. No reductions in colonisation were observed in vaccinated CD4 1 T-cell-deficient GK1.5 mice however (Fig.…”

“…Lack of protective immune responses after prophylactic vaccination of CD4 1 T-cell-deficient mice C57BL/6 or CD4 1 T-cell-deficient C57BL/6.BM1.GK 1.5 (GK1.5 mice) [21] mice were vaccinated with a single oral dose of recombinant S. Typhimurium expressing H. pylori ureA&B (SL3261 pYZ97) [22], or the carrier (SL3261) and challenged 4 wk later with a single dose of H. pylori Sydney strain 1 (SS1, a mouse-adapted strain) [23]. Three, seven and 21 days after challenge infection, mice were euthanised, stomachs were homogenised and levels of colonisation were determined by quantitative culture and expressed as Log 10 CFU per g tissue.…”

“…Vaccination and H. pylori infection C57BL/6.BM1.GK1.5 mice (GK1.5 mice) are transgenic for both heavy and light chains of the anti-CD4 GK1.5 mAb expressed under the CMV promotor [21] and as a result are deficient of CD4 1 cells. C57BL/6 mice and B6.GK1.5 mice were reared under specific pathogen-free conditions at the animal facility of Department Microbiology and Immunology at The University of Melbourne, with free access to water and food.…”

“…Female C57BL/6 mice or GK 1.5 [21], (6-8 wk of age) were vaccinated with a single oral dose of 1 Â 10 7 recombinant attenuated Salmonella enterica serovar Typhimurium (S. Typhimurium SL3261pYZ97) [22] (termed 'vaccinated'); control groups were either not vaccinated (termed 'control') or received the carrier strain (SL3261 alone) (termed 'carrier') as previously described [30].…”

“…It is noteworthy that carrier-vaccinated C57BL/6 mice also exhibited reductions in H. pylori colonisation compared with the control non-vaccinated mice ('carrier effect'), and this reduction was statistically significant at both 7 and 21 days post challenge (po0.003). Vaccinated mice did however have significantly lower colonisation than the carrier group on both dates (po0.05 and po0.01, respectively).GK1.5 mice are transgenic for both heavy and light chains of the anti-CD4 GK1.5 mAb expressed under the CMV promoter [21] and as a result are deficient of CD4 1 cells. No reductions in colonisation were observed in vaccinated CD4 1 T-cell-deficient GK1.5 mice however (Fig.…”