Formation and Function of Human CD28-Negative T Cells

描述（由申请人提供）：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维持t细胞记忆。cd28阴性“敲除”小鼠启动免疫反应，但T细胞记忆减少。目前尚不清楚CD28是如何被启动和/或维持记忆所需要的。CD28共同刺激T细胞对抗原的反应，但也刺激无抗原的T细胞亚群（“CD28激动作用”）。在衰老、慢性感染和自身免疫中，高达75%的人类（而非小鼠）CD8+ T细胞是cd28阴性的。它们不会增殖，这与免疫缺陷有关，包括无法控制艾滋病毒。缺乏CD28可能解释了CD28阴性CD8+ T细胞增殖失败的原因，但CD28阴性细胞上的抑制性NK受体也可能抑制增殖。我们假设CD28共同刺激回忆反应，但也维持没有抗原的记忆T细胞。CD28的激动作用由抗原呈递细胞上的B7.1 （CDS0）和某些单克隆抗体触发。这些激动剂触发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，导致T细胞增殖或凋亡。CD28激动作用也抑制CD28的转录。因此，CD28激动作用可能维持无抗原的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的表达和信号传导如何促进t细胞记忆。具体目标是(1)鉴定对CD28激动作用有反应的基因和T细胞亚群(2)鉴定CD28亚型和CD28激动作用的近端机制；(3)构建表达floxed- hucd28的小鼠，在小鼠模型中实现CD28表达的可控缺失。这些研究对于理解人类记忆T细胞的生物学，特别是疫苗设计具有重要意义。

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.