Lee Mercede, Bell Charles J M, Rubio Garcia Arcadio, Godfrey Leila, Pekalski Marcin, Wicker Linda S, Todd John A, Ferreira Ricardo C
JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
Discov Immunol. 2023 Aug 11;2(1):kyad012. doi: 10.1093/discim/kyad012. eCollection 2023.
Human CD56 natural killer (NK) cells represent a small subset of CD56 NK cells in circulation and are largely tissue-resident. The frequency and number of CD56 NK cells in blood has been shown to increase following administration of low-dose IL-2 (LD-IL2), a therapy aimed to specifically expand CD4 regulatory T cells (Tregs). Given the potential clinical application of LD-IL-2 immunotherapy across several immune diseases, including the autoimmune disease type 1 diabetes, a better understanding of the functional consequences of this expansion is urgently needed. In this study, we developed an co-culture assay with activated CD4 T cells to measure NK cell killing efficiency. We show that CD56 and CD56 NK cells show similar efficiency at killing activated CD4 conventional T (Tconv) and Treg cell subsets. However, in contrast to CD56 cells, CD56 NK cells preferentially target highly proliferative cells. We hypothesize that CD56 NK cells have an immunoregulatory role through the elimination of proliferating autoreactive CD4 Tconv cells that have escaped Treg suppression. These results have implications for the interpretation of current and future trials of LD-IL-2 by providing evidence for a new, possibly beneficial immunomodulatory mechanism of LD-IL-2-expanded CD56 NK cells.
人CD56自然杀伤（NK）细胞是循环中CD56 NK细胞的一个小亚群，主要驻留在组织中。低剂量白细胞介素-2（LD-IL2）给药后，血液中CD56 NK细胞的频率和数量已被证明会增加，LD-IL2是一种旨在特异性扩增CD4调节性T细胞（Tregs）的疗法。鉴于LD-IL-2免疫疗法在包括自身免疫性1型糖尿病在内的多种免疫疾病中的潜在临床应用，迫切需要更好地了解这种扩增的功能后果。在本研究中，我们开发了一种与活化的CD4 T细胞共培养的检测方法，以测量NK细胞的杀伤效率。我们发现，CD56⁺和CD56⁻ NK细胞在杀伤活化的CD4常规T（Tconv）细胞和Treg细胞亚群方面表现出相似的效率。然而，与CD56⁺细胞不同，CD56⁻ NK细胞优先靶向高增殖细胞。我们推测，CD56⁻ NK细胞通过消除逃避Treg抑制的增殖性自身反应性CD4 Tconv细胞而具有免疫调节作用。这些结果通过为LD-IL-2扩增的CD56⁻ NK细胞的一种新的、可能有益的免疫调节机制提供证据，对当前和未来LD-IL-2试验的解释具有重要意义。
