Brown D R, Green J M, Moskowitz N H, Davis M, Thompson C B, Reiner S L
University of Chicago, Illinois 60637, USA.
J Exp Med. 1996 Sep 1;184(3):803-10. doi: 10.1084/jem.184.3.803.
The 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 gamma production but markedly diminished levels of interleukin 4 (IL-4) after in vitro restimulation. In response to the pathogenic microbe, Leishman a 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 of IL-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 Th1 or Th2 responses.
CD28介导的信号在T辅助细胞成熟过程中的作用尚未完全明确。我们在多个CD4⁺T细胞分化系统中检测了通过CD28进行共刺激的必要性。用CD28基因敲除（CD28⁻/⁻）的小鼠进行体内初次免疫，可产生正常水平的抗原特异性干扰素γ，但在体外再次刺激后，白细胞介素4（IL-4）水平显著降低。针对致病性微生物利什曼原虫主要种（Leishmania major），C57BL6 CD28⁻/⁻小鼠完全能够控制感染，并表现出正常的T辅助1型反应。BALB/c CD28⁻/⁻小鼠对利什曼原虫主要种意外地表现出正常易感性。BALB/c CD28⁻/⁻小鼠在引流淋巴结中产生高水平的IL-4 mRNA和蛋白诱导。此外，体内中和IL-4可逆转BALB/c CD28⁻/⁻小鼠的易感性。我们还在CTLA4Ig存在的情况下，体外激活了来自BALB和C57BL背景的携带转基因CD28的T细胞。在无共刺激的情况下，BALB细胞比C57BL细胞具有更强的产生IL-4的能力。包括共刺激信号、基因多态性和免疫原性质在内的多种因素均影响T辅助细胞表型的确定，但这些结果提供了证据表明，产生Th1或Th2反应并非绝对需要CD28。
