Formation and Function of Human CD28-Negative T Cells

描述（由申请人提供）：人CD 28阴性T细胞的形成和功能。免疫学中的一个中心问题是T细胞记忆如何在没有抗原的情况下维持。CD 28阴性“敲除”小鼠启动免疫应答，但具有降低的T细胞记忆。目前尚不清楚CD 28是如何启动和/或维持记忆所必需的。CD 28共刺激T细胞对抗原的应答，但也刺激无抗原的T细胞亚群（“CD 28激动作用”）。在衰老、慢性感染和自身免疫中，高达75%的人而不是小鼠CD 8 + T细胞是CD 28阴性的。这些细胞不会增殖，与免疫缺陷有关，包括无法遏制艾滋病毒。缺乏CD 28可以解释CD 28阴性的CD 8 + T细胞的增殖失败，但CD 28阴性细胞上的抑制性NK受体也可能抑制增殖。我们假设，CD 28共刺激回忆反应，但也保持记忆T细胞无抗原。CD 28激动作用由抗原呈递细胞上的B7.1（CDS 0）和某些单克隆抗体触发。这些激动剂触发CD 28的酪氨酸磷酸化，募集PI 3激酶，维持CD 25和NK受体家族成员CD 69的表达，并导致T细胞增殖或凋亡。CD 28激动也抑制CD 28转录。因此，CD 28激动作用可能维持无抗原的CD 28+记忆细胞，但也可能驱动CD 28阴性T细胞的形成。长期目标是了解CD 28的表达和信号传导如何促进T细胞记忆。具体目的是：（1）鉴定对CD 28激动作用有反应的基因和T细胞亚群;（2）鉴定CD 28亚型和CD 28激动作用的近端机制;（3）构建表达hu CD 28的小鼠，以允许在小鼠模型中控制CD 28表达的缺失。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.