The p110γ isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites

被引:41
作者
Thomas, Molly S. [1 ]
Mitchell, Jason S. [1 ]
DeNucci, Christopher C. [1 ]
Martin, Amanda L. [1 ]
Shimizu, Yoji [1 ]
机构
[1] Univ Minnesota, Sch Med, Ctr Immunol, Dept Lab Med & Pathol,Canc Ctr, Minneapolis, MN 55455 USA
关键词
inflammation; chemokines; leukocyte; activation; trafficking;
D O I
10.1189/jlb.0807561
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The role of PI-3K in leukocyte function has been studied extensively. However, the specific role of the p110 gamma isoform of PI-3K in CD4 T lymphocyte function has yet to be defined explicitly. In this study, we report that although p110 gamma does not regulate antigen- dependent CD4 T cell activation and proliferation, it plays a crucial role in regulating CD4 effector T cell migration. Nai r ve p110 gamma(-/-) CD4 lymphocytes are phenotypically identical to their wildtype ( WT) counterparts and do not exhibit any defects in TCR- mediated calcium mobilization or Erk activation. In addition, p110 gamma- deficient CD4 OT. II T cells become activated and proliferate comparably with WT cells in response to antigen in vivo. Interestingly, however, antigen- experienced, p110 gamma- deficient CD4 OT. II lymphocytes exhibit dramatic defects in their ability to traffic to peripheral inflammatory sites in vivo. Although antigen- activated, p110 gamma-deficient CD4 T cells express P- selectin ligand, beta 2 integrin, beta 1 integrin, CCR4, CXCR5, and CCR7 comparably with WT cells, they exhibit impaired Factin polarization and migration in response to stimulation ex vivo with the CCR4 ligand CCL22. These findings suggest that p110 gamma regulates the migration of antigen- experienced effector CD4 T lymphocytes into inflammatory sites during adaptive immune responses in vivo.
引用
收藏
页码:814 / 823
页数:10
相关论文
共 48 条
[1]   Phosphoinositide 3-kinase γ participates in T cell receptor-induced T cell activation [J].
Alcázar, Isabela ;
Marqués, Miriam ;
Kumar, Amit ;
Hirsch, Emilio ;
Wymann, Matthias ;
Carrera, Ana C. ;
Barber, Domingo F. .
JOURNAL OF EXPERIMENTAL MEDICINE, 2007, 204 (12) :2977-2987
[2]   Isoform-specific functions of phosphoinositide 3-kinases:: p110δ but not p110γ promotes optimal allergic responses in vivo [J].
Ali, Khaled ;
Camps, Montserrat ;
Pearce, Wayne P. ;
Ji, Hong ;
Rueckle, Thomas ;
Kuehn, Nicolas ;
Pasquali, Christian ;
Chabert, Christian ;
Rommel, Christian ;
Vanhaesebroeck, Bart .
JOURNAL OF IMMUNOLOGY, 2008, 180 (04) :2538-2544
[3]   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
[4]   Class IB-phosphatidylinositol 3-kinase (PI3K) deficiency ameliorates IA-PI3K-induced systemic lupus but not T cell invasion [J].
Barber, DF ;
Bartolomé, A ;
Hernandez, C ;
Flores, JM ;
Fernandez-Arias, C ;
Rodríguez-Borlado, L ;
Hirsch, E ;
Wymann, M ;
Balomenos, D ;
Carrera, AC .
JOURNAL OF IMMUNOLOGY, 2006, 176 (01) :589-593
[5]   PI3Kγ inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus [J].
Barber, DF ;
Bartolomé, A ;
Hernandez, C ;
Flores, JM ;
Redondo, C ;
Fernandez-Arias, C ;
Camps, M ;
Ruckle, T ;
Schwarz, MK ;
Rodríguez, S ;
Martinez-A, C ;
Balomenos, D ;
Rommel, C ;
Carrera, AC .
NATURE MEDICINE, 2005, 11 (09) :933-935
[6]   Roles of Gβγ in membrane recruitment and activation of p110γ/p101 phosphoinositide 3-kinase γ [J].
Brock, C ;
Schaefer, M ;
Reusch, HP ;
Czupalla, C ;
Michalke, M ;
Spicher, K ;
Schultz, G ;
Nürnberg, B .
JOURNAL OF CELL BIOLOGY, 2003, 160 (01) :89-99
[7]   Targeting T cell responses by selective chemokine receptor expression [J].
Campbell, DJ ;
Debes, GF ;
Johnston, B ;
Wilson, E ;
Butcher, EC .
SEMINARS IN IMMUNOLOGY, 2003, 15 (05) :277-286
[8]   Rapid acquisition of tissue-specific homing phenotypes by CD4+ T cells activated in cutaneous or mucosal lmphoid tissues [J].
Campbell, DJ ;
Butcher, EC .
JOURNAL OF EXPERIMENTAL MEDICINE, 2002, 195 (01) :135-141
[9]   Cutting edge: Chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions [J].
Campbell, James J. ;
O'Connell, Daniel J. ;
Wurbel, Marc-Andre .
JOURNAL OF IMMUNOLOGY, 2007, 178 (06) :3358-3362
[10]   The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells [J].
Campbell, JJ ;
Haraldsen, G ;
Pan, J ;
Rottman, J ;
Qin, S ;
Ponath, P ;
Andrew, DP ;
Warnke, R ;
Ruffing, N ;
Kassam, N ;
Wu, L ;
Butcher, EC .
NATURE, 1999, 400 (6746) :776-780