The chemokine receptor CCR7 controls lymph node‐dependent cytotoxic T cell priming in alloimmune responses

Höpken, Uta E.; Droese, Jana; Li, Jianping; Joergensen, Joanne; Breitfeld, Dagmar; Zerwes, Hans‐Günter; Lipp, Martin

doi:10.1002/eji.200324690

Cited by 53 publications

(52 citation statements)

References 36 publications

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“…EAE was induced by immunization with spinal cord homogenate or myelin oligodendrocyte glycoprotein (MOG) [8][9][10][11][12][13][14][15][16][17][18][19][20][21] in CFA as described [27,28]. Deep and superficial CLN were also isolated from CCR7-deficient (n=4) and wild-type mice (n=4) [29] with chronic EAE, obtained from stock bred at the animal facility of the Max Delbrück Center for Molecular Medicine (Berlin, Germany). Chronic EAE was induced by s.c. injections of 200 μg MOG emulsified in CFA (Difco Laboratories) containing 400 μg of Mycobacterium tuberculosis.…”

Section: Eae Tissuesmentioning

confidence: 99%

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

et al. 2008

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Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in J Mol Med (2009) human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked.

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Section: Eae Tissuesmentioning

confidence: 99%

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

et al. 2008

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“…injection of 4 Â 10 7 BALB/c splenocytes. In parallel plasma samples from WT (n 5 5) and Ccr5 À/À (n 5 3) renal allograft recipients 42 days after transplantation were analyzed using a modification of published methods [16,51]. Briefly, aliquots containing 4.5 Â 10 5 J558L BALB/c plasmacytoma cells [52] in 150 mL HBSS were mixed with 150 mL HBSS diluted plasma samples from WT (1:4) or Ccr5 À/À (1:4, 1:16, 1:64, 1:256) C57BL/6 recipients and this mixture was incubated for 1 h on ice.…”

Section: Alloreactive Antibody Titersmentioning

confidence: 99%

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

et al. 2009

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The chemokine (C-C motif) receptor 5 (CCR5) has been implicated in experimental and clinical allograft rejection. To dissect the function of CCR5 in acute and chronic renal allograft rejection, bilaterally nephrectomized WT and Ccr5 À/À C57BL/6 mice were used as recipients of WT BALB/c renal allografts and analyzed 7 and 42 days after transplantation. Lesion scores (glomerular damage, vascular rejection, tubulointerstitial inflammation) and numbers of CD4 1 , CD8 1 , CD11c 1 and alpha smooth muscle actin (aSMA) 1 cells were reduced in allografts from Ccr5 À/À recipients during the chronic phase. Increasing creatinine levels indicated deterioration of allograft function over time. While mRNA expression of Th1-associated markers decreased between 7 and 42 days, Th2-associated markers increased. Markers for alternatively activated macrophages (arginase 1, chitinase 3-like 3, resistin-like a, mannose receptor, C type 1), were strongly upregulated (mRNA and/or protein level) only in allografts from Ccr5 À/À recipients at 42 days. Ccr5 deficiency shifted intragraft immune responses during the chronic phase towards the Th2 type and led to accumulation of alternatively activated macrophages. Additionally, splenocytes from unchallenged Ccr5 À/À mice showed significantly increased arginase 1 and mannose receptor 1 mRNA levels, suggesting constitutive alternative activation of splenic macrophages. We conclude that Ccr5 deficiency favors alternative macrophage activation. This finding may be relevant for other inflammatory diseases that involve macrophage activation and may also influence future therapeutic strategies targeting CCR5.

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“…Lack of CCR7 in genetargeted mice leads to disrupted lymphoid tissue microarchitecture and altered acquired immune responses [21]. More specifically, CCR7-deficient mice show reduced delayed-type hypersensitivity (DTH) and contact hypersensitivity reactions [21] and fail to mount rapid allogeneic or anti-microbial cytotoxic T cell responses [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

et al. 2007

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Foxp3 + CD25 + CD4 + Treg play a fundamental role in the maintenance of self tolerance and the control of inflammatory reactions. Previous data demonstrated a division of labor between naive-and effector/memory-like Treg subsets, which is largely based on their lymph node-recirculating and inflammation-seeking migration behavior, respectively. The chemokine receptor CCR7 is expressed on both types of Treg subsets, albeit at different levels. Whether it fulfills similar or distinct roles in these subsets has not been studied so far. We here show that the recirculation of naive-like Treg through LN and, to some extent, the gut is dependent on CCR7. Lack of CCR7 not only prevents recirculation, but also almost completely abolishes the ability of naive-like Treg to control the priming phase of an immune response. In contrast, CCR7 deficiency in effector/memory-like Treg promotes their accumulation in inflamed sites, compatible with a role of CCR7 for exit from the tissue. Local Treg accumulation was accompanied by an enhanced suppression of inflammation. Together, our findings provide conclusive evidence that CCR7 expression on Treg differentially controls in vivo function of the naive-and effector/memory-like subsets.

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The chemokine receptor CCR7 controls lymph node‐dependent cytotoxic T cell priming in alloimmune responses

Cited by 53 publications

References 36 publications

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

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