Fiske Brigita E, Getahun Andrew
bioRxiv. 2023 Jan 23:2023.01.23.525206. doi: 10.1101/2023.01.23.525206.
The role of T cell help in autoantibody responses is not well understood. Since tolerance mechanisms govern both T and B cell responses, one might predict that both T cell tolerance and B cell tolerance must be defeated in autoantibody responses requiring T cell help. To define whether autoreactive B cells depend on T cells to generate autoantibody responses, we studied the role of T cells in autoantibody responses resulting from acute cell-specific deletion of regulatory phosphatases. Ars/A1 B cells are DNA-reactive and require continuous inhibitory signaling by the tyrosine phosphatase SHP-1 and the inositol phosphatases SHIP-1 and PTEN to maintain unresponsiveness. Acute B cell-restricted deletion of any of these phosphatases results in an autoantibody response. Here we show that CD40-CD40L interactions are required to support autoantibody responses of B cells whose anergy has been compromised. If the B cell-intrinsic driver of loss of tolerance is failed negative regulation of PI3K signaling, bystander T cells provide sufficient CD40-mediated signal 2 to support an autoantibody response. However, while autoantibody responses driven by acute B cell-targeted deletion of SHP-1 also require T cells, bystander T cell help does not suffice. These results demonstrate that upregulation of PI3K signaling in autoreactive B cells, recapitulating the effect of multiple autoimmunity risk alleles, promotes autoantibody responses both by increasing B cells’ cooperation with non-cognate T cell help, as well as by altering BCR signaling. Receptiveness to bystander T cell help enables autoreactive B cells to circumvent the fail-safe of T cell tolerance.
Phosphatase suppression of PI3K signaling is an important mechanism by which peripheral autoreactive B cells are kept in an unresponsive/anergic state. Loss of this suppression, due to genetic alleles that confer risk of autoimmunity, often occurs in autoreactive B cells of individuals who develop autoimmune disease. Here we demonstrate that de-repression of PI3K signaling promotes autoantibody responses of a DNA-reactive B cell clone by relaxing dependence of autoantibody responses on T cell-derived helper signals. These results suggest that impaired regulation of PI3K signaling can promote autoantibody responses in two ways: by restoring antigen receptor signaling and by enabling autoreactive B cells to circumvent restrictions imposed by T cell tolerance mechanisms.
T细胞辅助在自身抗体应答中的作用尚未得到充分理解。由于耐受机制同时调控T细胞和B细胞应答，因此有人可能会预测，在需要T细胞辅助的自身抗体应答中，T细胞耐受和B细胞耐受必定都被打破。为了确定自身反应性B细胞是否依赖T细胞来产生自身抗体应答，我们研究了T细胞在因急性细胞特异性缺失调节性磷酸酶而导致的自身抗体应答中的作用。Ars/A1 B细胞具有DNA反应性，需要酪氨酸磷酸酶SHP-1以及肌醇磷酸酶SHIP-1和PTEN持续的抑制性信号来维持无反应状态。这些磷酸酶中任何一种的急性B细胞限制性缺失都会导致自身抗体应答。在此我们表明，CD40-CD40L相互作用是支持其无反应性已被破坏的B细胞产生自身抗体应答所必需的。如果耐受丧失的B细胞内在驱动因素是PI3K信号的负调控失败，旁观者T细胞会提供足够的CD40介导的信号2来支持自身抗体应答。然而，虽然由急性B细胞靶向缺失SHP-1驱动的自身抗体应答也需要T细胞，但旁观者T细胞的辅助并不足够。这些结果表明，自身反应性B细胞中PI3K信号的上调（重现了多个自身免疫风险等位基因的作用），通过增加B细胞与非同源T细胞辅助的合作以及改变BCR信号，促进了自身抗体应答。对旁观者T细胞辅助的接受性使自身反应性B细胞能够规避T细胞耐受的安全机制。
磷酸酶对PI3K信号的抑制是外周自身反应性B细胞保持无反应/无活性状态的重要机制。由于赋予自身免疫风险的基因等位基因导致这种抑制的丧失，常常发生在患自身免疫病个体的自身反应性B细胞中。在此我们证明，PI3K信号的去抑制通过减轻自身抗体应答对T细胞衍生辅助信号的依赖性，促进了一个具有DNA反应性的B细胞克隆的自身抗体应答。这些结果表明，PI3K信号调节受损可通过两种方式促进自身抗体应答：通过恢复抗原受体信号以及使自身反应性B细胞规避T细胞耐受机制所施加的限制。
