T cells from Leishmania major-susceptible BALB/c mice have a defect in efficiently up-regulating CXCR3 upon activation
T cells from Leishmania major-susceptible BALB/c mice have a defect in efficiently up-regulating CXCR3 upon activation
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DOI：
10.4049/jimmunol.181.7.4613
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发表时间：
2008-10-01
影响因子：
4.4
通讯作者：
Satoskar, Abhay R.
中科院分区：
文献类型：
--
作者：
Barbi, Joseph;Brombacher, Frank;Satoskar, Abhay R.
遗传背景影响重型利什曼原虫感染的结果。C57 BL/6小鼠产生Th 1应答并解决感染。与此相反，BALB/c小鼠产生Th 2应答，并出现慢性病变。即使BALB/c小鼠在感染后早期在其淋巴结（LN）中以类似于C57 BL/6小鼠的比例产生IFN-γ产生T细胞，也可以观察到这种易感表型。我们先前已经证明趋化因子受体CXCR 3通过将产生IFN-γ的T细胞募集到C57 BL/6小鼠的病变处来介导针对L major的免疫。因此，我们假设，IFN-γ分泌T细胞在BALB/c小鼠不能提供保护，因为他们可能是有缺陷的上调CXCR 3。为了验证这一假设，我们分析了在L主要感染期间，BALB/c和C57 BL/6小鼠的LN和病变中表达CXCR 3的T细胞的动力学。此外，我们比较了来自BALB/c和C57 BL/6小鼠的T细胞在活化后上调CXCR 3的能力。我们发现C57 BL/6小鼠中L主要感染的消退与局部LN和病变中CXCR 3（+）T细胞比例的增加有关，而BALB/c小鼠的疾病进展与这些群体的减少有关。来自幼稚BALB/c小鼠而非C57 BL/6小鼠的抗CD 3/CD 28活化的T细胞在上调CXCR 3方面有缺陷。CXCR 3在BALB/c T细胞上的诱导受损不是由于缺乏IFN-γ，并且部分由IL-10介导，而不是IL-4或IL-13。我们认为，BALB/c小鼠T细胞CXCR 3上调缺陷可能导致L主要易感性。
Genetic background influences the outcome of Leishmania major infection. C57BL/6 mice mount a Th1 response and resolve infection. In contrast, BALB/c mice mount a Th2 response and develop chronic lesions. This susceptible phenotype is seen even though BALB/c mice generate IFN-gamma-producing T cells at proportions similar to C57BL/6 mice in their lymph nodes (LN) early after infection. We had previously shown that chemokine receptor CXCR3 mediates immunity against L major by recruiting IFN-gamma-producing T cells to the lesions of C57BL/6 mice. Therefore, we hypothesized that IFN-gamma-secreting T cells in BALB/c mice are unable to confer protection because they may be defective in up-regulating CXCR3. To test this hypothesis, we analyzed kinetics of CXCR3-expressing T cells in the LN and lesions of BALB/c and C57BL/6 mice during L major infection. Additionally, we compared the ability of T cells from BALB/c and C57BL/6 mice to up-regulate CXCR3 upon activation. We found that resolution of L major infection in C57BL/6 mice was associated with an increase in the proportion of CXCR3(+) T cells in regional LN and lesions, whereas disease progression in BALB/c mice was associated with a decrease in these populations. Anti-CD3/CD28-activated T cells from naive BALB/c but not C57BL/6 mice were defective in up-regulating CXCR3. Impaired induction of CXCR3 on BALB/c T cells was not due to lack of IFN-gamma and was mediated partially by IL-10 but not IL4 or IL-13. We propose that defective CXCR3 up-regulation on T cells in BALB/c mice may contribute to L major susceptibility.