DOCK8 is essential for LFA-1-dependent positioning of T follicular helper cells in germinal centers

被引:12
作者
Janssen, Erin [1 ,2 ]
Tohme, Mira [1 ,2 ]
Butts, Jordan [1 ,2 ]
Giguere, Sophie [3 ,4 ]
Sage, Peter T. [2 ,5 ]
Velazquez, Francisco E. [6 ,7 ]
Kam, Christy [1 ,2 ]
Milin, Elena [1 ,2 ]
Das, Mrinmoy [1 ,2 ]
Sobh, Ali [8 ]
Al-Tamemi, Salem [9 ]
Luscinskas, Francis W. [6 ,7 ]
Batista, Facundo [3 ,4 ]
Geha, Raif S. [1 ,2 ]
机构
[1] Boston Childrens Hosp, Div Immunol, 1 Blackfan Circle,Karp Bldg 10th Floor, Boston, MA 02115 USA
[2] Harvard Med Sch, Boston, MA 02115 USA
[3] Massachusetts Gen Hosp, Ragon Inst, Massachusetts Inst Technol, Cambridge, MA USA
[4] Harvard Med Sch, Cambridge, MA USA
[5] Brigham & Womens Hosp, Renal Div, Transplantat Res Ctr, 75 Francis St, Boston, MA 02115 USA
[6] Harvard Med Sch, Brigham & Womens Hosp, Ctr Excellence Vasc Biol, Dept Pathol, Boston, MA 02115 USA
[7] Harvard Med Sch, Brigham & Womens Hosp, Ctr Excellence Vasc Biol, Dept Med, Boston, MA 02115 USA
[8] Mansoura Univ, Childrens Hosp, Dept Pediat, Fac Med, Mansoura, Egypt
[9] Sultan Qaboos Univ Hosp, Muscat, Oman
关键词
CENTER B-CELL; ALDRICH SYNDROME PROTEIN; CXC CHEMOKINE RECEPTOR-5; LYMPH-NODES; LFA-1; AFFINITY; DYNAMICS; DIFFERENTIATION; EXPRESSION; ANTIGEN;
D O I
10.1172/jci.insight.134508
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
T follicular helper (Tfh) cell migration into germinal centers (GCs) is essential for the generation of GC B cells and antibody responses to T cell-dependent (TD) antigens. This process requires interactions between lymphocyte function-associated antigen 1 (LFA-1) on Tfh cells and ICAMs on B cells. The mechanisms underlying defective antibody responses to TD antigens in DOCK8 deficiency are incompletely understood. We show that mice selectively lacking DOCK8 in T cells had impaired IgG antibody responses to TD antigens, decreased GC size, and reduced numbers of GC B cells. However, they developed normal numbers of Tfh cells with intact capacity for driving B cell differentiation into a GC phenotype in vitro. Notably, migration of DOCK8-deficient T cells into GCs was defective. Following T cell receptor (TCR)/CD3 ligation, DOCK8-deficient T cells had impaired LFA-1 activation and reduced binding to ICAM-1. Our results therefore indicate that DOCK8 is important for LFA-1-dependent positioning of Tfh cells in GCs, and thereby the generation of GC cells and IgG antibody responses to TD antigen.
引用
收藏
页数:14
相关论文
共 73 条
[1]   Difference in Th1 and Th17 Lymphocyte Adhesion to Endothelium [J].
Alcaide, Pilar ;
Maganto-Garcia, Elena ;
Newton, Gail ;
Travers, Richard ;
Croce, Kevin J. ;
Bu, De-xiu ;
Luscinskas, Francis W. ;
Lichtman, Andrew H. .
JOURNAL OF IMMUNOLOGY, 2012, 188 (03) :1421-1430
[2]   In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines [J].
Ansel, KM ;
McHeyzer-Williams, LJ ;
Ngo, VN ;
McHeyzer-Williams, MG ;
Cyster, JG .
JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 190 (08) :1123-1134
[3]   CD47 plays a critical role in T-cell recruitment by regulation of LFA-1 and VLA-4 integrin adhesive functions [J].
Azcutia, Veronica ;
Routledge, Matthew ;
Williams, Marcie R. ;
Newton, Gail ;
Frazier, William A. ;
Manica, Andre ;
Croce, Kevin J. ;
Parkos, Charles A. ;
Schmider, Angela B. ;
Turman, Melissa V. ;
Soberman, Roy J. ;
Luscinskas, Francis W. .
MOLECULAR BIOLOGY OF THE CELL, 2013, 24 (21) :3358-3368
[4]   Germinal centers: programmed for affinity maturation and antibody diversification [J].
Bannard, Oliver ;
Cyster, Jason G. .
CURRENT OPINION IN IMMUNOLOGY, 2017, 45 :21-30
[5]   T cell interactions with B cells during germinal center formation, a three-step model [J].
Biram, Adi ;
Davidzohn, Natalia ;
Shulman, Ziv .
IMMUNOLOGICAL REVIEWS, 2019, 288 (01) :37-48
[6]   ICOS deficiency is associated with a severe reduction of CXCR5+ CD4 germinal center Th cells [J].
Bossaller, Lukas ;
Burger, Jan ;
Draeger, Ruth ;
Grimbacher, Bodo ;
Knoth, Rolf ;
Plebani, Alessandro ;
Durandy, Anne ;
Baumann, Ulrich ;
Schlesier, Michael ;
Welcher, Andrew A. ;
Peter, Hans Hartmut ;
Warnatz, Klaus .
JOURNAL OF IMMUNOLOGY, 2006, 177 (07) :4927-4932
[7]   Identification and characterization of KLHL4, a novel human homologue of the Drosophila Kelch gene that maps within the X-linked cleft palate and ankyloglossia (CPX) critical region [J].
Braybrook, C ;
Warry, G ;
Howell, G ;
Arnason, A ;
Bjornsson, A ;
Moore, GE ;
Ross, MT ;
Stanier, P .
GENOMICS, 2001, 72 (02) :128-136
[8]   Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production [J].
Breitfeld, D ;
Ohl, L ;
Kremmer, E ;
Ellwart, J ;
Sallusto, F ;
Lipp, M ;
Förster, R .
JOURNAL OF EXPERIMENTAL MEDICINE, 2000, 192 (11) :1545-1551
[9]   Optimal Germinal Center Responses Require a Multistage T Cell:B Cell Adhesion Process Involving Integrins, SLAM-Associated Protein, and CD84 [J].
Cannons, Jennifer L. ;
Qi, Hai ;
Lu, Kristina T. ;
Dutta, Mala ;
Gomez-Rodriguez, Julio ;
Cheng, Jun ;
Wakeland, Edward K. ;
Germain, Ronald N. ;
Schwartzberg, Pamela L. .
IMMUNITY, 2010, 32 (02) :253-265
[10]   ICOS Receptor Instructs T Follicular Helper Cell versus Effector Cell Differentiation via Induction of the Transcriptional Repressor BcI6 [J].
Choi, Youn Soo ;
Kageyama, Robin ;
Eto, Danello ;
Escobar, Tania C. ;
Johnston, Robert J. ;
Monticelli, Laurel ;
Lao, Christopher ;
Crotty, Shane .
IMMUNITY, 2011, 34 (06) :932-946