Formation and Function of Human CD28-Negative T Cells

描述(申请人提供)：人CD28阴性T细胞的形成和功能。免疫学的一个中心问题是如何在没有抗原的情况下保持T细胞的记忆。CD28阴性的“基因敲除”小鼠启动免疫反应，但T细胞记忆力下降。目前尚不清楚CD28是如何启动和/或维持记忆的。CD28共同刺激T细胞对抗原的反应，但也刺激没有抗原的T细胞亚群(CD28激动剂)。在衰老、慢性感染和自身免疫中，高达75%的人而不是小鼠的CD8+T细胞是CD28阴性的。这些病毒不会扩散，与免疫缺陷有关，包括未能控制艾滋病毒。CD28缺失可能是CD28阴性的CD8+T细胞增殖失败的原因，但抑制CD28阴性细胞的NK受体也可能抑制其增殖。我们假设CD28共同刺激回忆反应，但也在没有抗原的情况下维持记忆T细胞。CD28激动剂是由抗原提呈细胞上的B7.1(CDS0)和某些单抗触发的。这些激动剂激活CD28的酪氨酸磷酸化，招募PI3激酶，维持CD25和NK受体家族成员CD69的表达，并导致T细胞增殖或凋亡。CD28激动剂也抑制CD28转录。因此，CD28激动剂可能支持无抗原的CD28+记忆细胞，但也可能驱动CD28阴性T细胞的形成。长期目标是了解CD28的表达和信号是如何促进细胞记忆的。其具体目的是(1)识别CD28激动剂反应的基因和T细胞亚群；(2)识别CD28激动剂的CD28异构体和近端机制；(3)在小鼠模型中构建表达FLOXED-huCD28的小鼠，以允许CD28表达的可控删除。这些研究对于理解人类记忆T细胞的生物学，特别是疫苗设计非常重要。

DESCRIPTION (provided by applicant): Formation and Function of Human CD28-negative T cells. A central problem in immunology is how Tcell memory is maintained without antigen. CD28-negative "knockout" mice initiate immune responses but have reduced T cell memory. It is unclear how CD28 is required for initiation and/or maintenance of memory. CD28 co-stimulates T cell responses to antigen, but also stimulates a subset of T cells without antigen ("CD28agonism"). In aging, chronic infection and autoimmunity, up to 75% of human but not mouse CD8+ T cells are CD28-negative. These do not proliferate, associated with immune deficits, including failure to contain HIV. Lack of CD28 may explain proliferative failure of CD28-negative CD8+ T cells, but inhibitory NK receptors onCD28-negative cells might also inhibit proliferation. We hypothesize that CD28 co-stimulates recall responses but also maintains memory T cells without antigen. CD28 agonism is triggered by B7.1 (CDS0) on antigen-presenting cells and by certain monoclonal antibodies. These agonists trigger tyrosine phosphorylation ofCD28, recruit PI3 kinase, sustain expression of CD25 and the NK receptor-family member CD69 and result in T cell proliferation or apoptosis. CD28 agonism also suppresses CD28 transcription. Therefore, CD28agonism might sustain CD28+ memory cells without antigen, but might also drive the formation of CD28-negative T cells. The long-range goal is to understand how expression of and signaling by CD28 contributes toT cell memory. The Specific Aims are (1) identify genes and T cell subsets responding to CD28 agonism(2) identify the CD28 isoforms and proximal mechanisms for CD28 agonism; (3) construct mice expressingfloxed-huCD28 to permit controlled deletion of CD28 expression in a mouse model. These studies are important for understanding the biology of human memory T cells especially for vaccine design.