Department of Anatomy, HUN-REN-PTE PACAP Research Team, Centre for Neuroscience, Medical School, University of Pecs, 7624 Pecs, Hungary.
Department of Medical Microbiology and Immunology, Medical School, University of Pecs, 7624 Pecs, Hungary.
Int J Mol Sci. 2024 Oct 3;25(19):10676. doi: 10.3390/ijms251910676.
PACAP (pituitary adenylate cyclase activating polypeptide) is a widespread neuropeptide with cytoprotective and anti-inflammatory effects. It plays a role in innate and adaptive immunity, but data are limited about gut-associated lymphoid tissue. We aimed to reveal differences in Peyer's patches between wild-type (WT) and PACAP-deficient (KO) mice. Peyer's patch morphology from young (3-months-old) and aging (12-15-months-old) mice was examined, along with flow cytometry to assess immune cell populations, expression of checkpoint molecules (PD-1, PD-L1, TIM-3, Gal-9) and functional markers (CD69, granzyme B, perforin) in CD3+, CD4+, and CD8+ T cells. We found slight differences between aging, but not in young, WT, and KO mice. In WT mice, aging reduced CD8+ T cell numbers frequency and altered checkpoint molecule expression (higher TIM-3, granzyme B; lower Gal-9, CD69). CD4+ T cell frequency was higher with similar checkpoint alterations, indicating a regulatory shift. In PACAP KO mice, aging did not change cell population frequencies but led to higher TIM-3, granzyme B and lower PD-1, PD-L1, Gal-9, and CD69 expression in CD4+ and CD8+ T cells, with reduced overall T cell activity. Thus, PACAP deficiency impacts immune dysfunction by altering checkpoint molecules and T cell functionality, particularly in CD8+ T cells, suggesting complex immune responses by PACAP, highlighting its role in intestinal homeostasis and potential implications for inflammatory bowel diseases.
PACAP（垂体腺苷酸环化酶激活肽）是一种广泛存在的神经肽，具有细胞保护和抗炎作用。它在先天和适应性免疫中发挥作用，但关于肠相关淋巴组织的数据有限。我们旨在揭示野生型（WT）和 PACAP 缺陷型（KO）小鼠派尔集合淋巴结之间的差异。检查了来自年轻（3 个月大）和衰老（12-15 个月大）小鼠的派尔集合淋巴结形态，并用流式细胞术评估免疫细胞群体、检查点分子（PD-1、PD-L1、TIM-3、Gal-9）的表达以及 CD3+、CD4+和 CD8+T 细胞中的功能标志物（CD69、颗粒酶 B、穿孔素）。我们发现衰老之间存在细微差异，但在年轻、WT 和 KO 小鼠中则没有。在 WT 小鼠中，衰老减少了 CD8+T 细胞的数量频率，并改变了检查点分子的表达（更高的 TIM-3、颗粒酶 B；更低的 Gal-9、CD69）。CD4+T 细胞频率更高，具有相似的检查点改变，表明发生了调节性转变。在 PACAP KO 小鼠中，衰老不会改变细胞群体频率，但会导致 CD4+和 CD8+T 细胞中 TIM-3、颗粒酶 B 和 PD-1、PD-L1、Gal-9 和 CD69 的表达降低，总 T 细胞活性降低。因此，PACAP 缺乏通过改变检查点分子和 T 细胞功能来影响免疫功能障碍，特别是在 CD8+T 细胞中，这表明 PACAP 具有复杂的免疫反应，突出了其在肠道稳态中的作用及其对炎症性肠病的潜在影响。
