IL-15 induces C4+ effector memory T cell production and tissue emigration in nonhuman primates
IL-15 induces C4+ effector memory T cell production and tissue emigration in nonhuman primates
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DOI：
10.1172/jci27564
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发表时间：
2006-06-01
影响因子：
15.9
通讯作者：
Villinger, Francois
中科院分区：
文献类型：
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作者：
Picker, Louis J.;Reed-Inderbitzin, Edward F.;Villinger, Francois
HIV感染选择性地靶向CD 4（+）效应记忆T（T-EM）细胞，导致在早期感染中粘膜效应位点中的CD 4（+）T细胞急剧耗竭。TEM细胞隔室的再生是缓慢和不完全的，即使当病毒复制被抗逆转录病毒疗法（ART）控制时。在这里，我们证明，IL-15显着增加恒河猴（RM）的CD 4（+）和CD 8（+）TEM细胞的体内增殖，对幼稚或中央记忆T（T-CM）细胞亚群的影响很小，反应模式是非常不同的IL-2或IL-7。响应于IL-15产生的T-EM细胞不会在血液中积累。相反，5-溴-2 '-脱氧尿苷（BrdU）标记研究表明，许多这些细胞迅速分散到淋巴管外效应位点，在那里它们表现出（缓慢）衰变动力学，与未处理的对照无区别。在SIV感染不受控制和免疫系统高度激活的RM中，IL-15并没有显著增加CD 4（+）T-EM细胞增殖，但在病毒学控制和ART免疫激活伴随减少的情况下，再次观察到IL-15反应性。这些数据表明，IL-15在ART环境中的治疗性使用可能有助于特异性恢复作为HIV主要靶点的CD 4（+）T细胞区室，减少耗尽前体T细胞区室或产生潜在有害调节亚群的风险。
HIV infection selectively targets CD4(+) effector memory T (T-EM) cells, resulting in dramatic depletion of CD4(+) T cells in mucosal effector sites in early infection. Regeneration of the TEM cell compartment is slow and incomplete, even when viral replication is controlled by antiretroviral therapy (ART). Here, we demonstrate that IL-15 dramatically increases in vivo proliferation of rhesus macaque (RM) CD4(+) and CD8(+) TEM cells with little effect on the naive or central memory T (T-CM) cell subsets, a response pattern that is quite distinct from that of either IL-2 or IL-7. T-EM cells produced in response to IL-15 did not accumulate in blood. Rather, 5-bromo-2'-deoxyuridine (BrdU) labeling studies suggest that many of these cells rapidly disperse to extralymphoid effector sites, where they manifest (slow) decay kinetics indistinguishable from that of untreated controls. In RMs with uncontrolled SIV infection and highly activated immune systems, IL-15 did not significantly increase CD4(+) T-EM cell proliferation, but with virologic control and concomitant reduction in immune activation by ART, IL-15 responsiveness was again observed. These data suggest that therapeutic use of IL-15 in the setting of ART might facilitate specific restoration of the CD4(+) T cell compartment that is the primary target of HIV with less risk of exhausting precursor T cell compartments or generating potentially deleterious regulatory subsets.