Limited role of CD28-mediated signals in T helper subset differentiation.

Abstract

SummaryThe role of CD28-mediated signals in T helper cell maturation is not fully understood. We tested the requirement for costimulation through CD28 in several systems of CD4 + T cell differentiation. In vivo priming of mice with genetic disruption of CD28 (CD28 -/-) yielded normal levels of antigen-specific interferon ~/production but markedly diminished levels of interleukin 4 (IL-4) after in vitro restimulation. In response to the pathogenic microbe, Leishmania major, C57BL6 CD28 -/-mice were fully capable of controlling infection and exhibited a normal T helper 1 response. BALB/c CD28 -/-mice unexpectedly exhibited normal susceptibility to L. major. BALB/c CD28 -/-mice developed high levels oflL-4 mRNA and protein induction in the draining lymph nodes. In addition, susceptibility of BALB/c CD28 -/-mice was reversed by neutralization of IL-4 in vivo. We also activated transgenic CD28-bearing T cells from the BALB and C57BL background in vitro in the presence of CTLA4Ig. BALB cells had greater IL-4-producing capacity than C57BL cells in the absence of costimulation. Diverse factors including costimulatory signals, genetic polymorphism, and the nature of the immunogen all influence T helper phenotype commitment, but these results provide evidence that CD28 is not an absolute requirement for generating either Thl or Th2 responses.U 'nder most circumstances, successful T cell activation requires a signal delivered through the T cell antigen receptor and a second signal referred to as costimulation (1). T cells activated in vitro in the presence of CD28-B7 blockade display characteristics of anergy (2), and blockade in vivo has attenuated many T cell-mediated immune responses, including graft rejection (3, 4) and autoimnmnity (5-7). Analysis of CD28-deficient mice revealed relatively normal T cell development, preserved cytolytic T cell responses, but impaired B cell help (8). The role of costimulation in the generation and maintenance of antigen-specific CD4 + T helper (Th) subsets remains controversial. Data supports models in which both Thl and Th2 responses require CD28-mediated signals (2, 9-11), but some evidence suggests that only certain Th subsets are dependent on costimulation (12-20). Other findings suggest discrete stages of maturation selectively require CD28-mediated costimulation (12), and some current models propose that specific B7 ligands mediate biased Th maturation (5,6,21,22).Daniel R. Brown and Jonathan M. Green contributed equally to this work.In murine infection with Leishmania major, pathogenspecific CD4 + Th effectors mediate the polarized potential outcomes of infection (23). Thl responses that arise in C57BL/6 mice result in self-limited heating disease through successful macrophage activation by T cell-derived IFN-y. Th2 responses that arise in mice from the BALB background mediate inexorable susceptibility characterized by uncontrolled parasite dissemination. The unique localization of the parasite to MHC class II-rich intracellular compartments leads to a strong bias in CD4 +, clas...

Human Neutrophil-Expressed CD28 Interacts with Macrophage B7 to Induce Phosphatidylinositol 3-Kinase-Dependent IFN-γ Secretion and Restriction of Leishmania Growth

“…Although neutrophils have already been reported to secrete IFN-␥ (11), our study provides the first mechanistic description of how a signal generated by CD28 on cell surface regulates the cytokine gene transcription and secretion in neutrophils. While observations reported in this work indicate the significance of CD28 signaling in neutrophil-mediated induction of anti-leishmanial immune response, earlier observations on murine L. major infection in CD28-deficient mice suggested a limited role for CD28 in Th subset differentiation during the infection (29,30). The apparent discrepancy between these observations can be explained by a possible absence of CD28 on murine neutrophils, as casein-elicited early peritoneal exudate cells do not stain for CD28 (data not shown).…”

CD28 Costimulation and Parasite Dose Combine to Influence the Susceptibility of BALB/c Mice to Infection withLeishmania major

“…Importantly, Ag dose has also been shown to help regulate Th differentiation (41-45) where a reduction in the level of antigenic stimulus for the T cell increases the requirement for CD28-B7 costimulation. These observations, combined with the contradictory findings that CD28-B7 interactions did not appear to be required for susceptibility or resistance to L. major infections when CD28 Ϫ/Ϫ mice were used (46,47), as opposed to the observations that BALB/c mice become resistant to L. major infection following treatment with CTLA4-Ig or anti-B7-2 Ab (18, 48), prompted us to re-evaluate the role of CD28 costimulation in L. major infections. We used CD28 Ϫ/Ϫ mice on the susceptible BALB/c background infected with a low parasite inoculum.…”

Role of Ox40 Signals in Coordinating Cd4 T Cell Selection, Migration, and Cytokine Differentiation in T Helper (Th)1 and Th2 Cells

“…The lack of CXCR-5–positive CD4 T cells in CD28-deficient mice is directly correlated with their failure to form GCs 16. Whereas CD28 signaling is absolutely required for the generation of CD4 T cell help for GCs, an IL-12–dependent Th1 inflammatory CD4 immune response to the intracellular pathogen Leishmania is not CD28 dependent 17.…”