Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo.
The development of effector and memory CD4 cell populations depends upon both T cell receptor (TCR) engagement of peptide/major histocompatibility complex (MHC) class II complexes and ligation of costimulatory molecules with counter receptors on antigen-presenting cells (APCs). We showed previously that sustained interactions with APCs could be crucial for optimal expansion of CD4 cells and for development of effectors that secrete cytokines associated with Th2 cells. Using an adoptive transfer model with TCR transgenic CD4 cells, we now show that responses of CD4 cells primed in B cell-deficient mice become aborted, but are fully restored upon the transfer of activated B cells. Although B cells have the capacity to secrete multiple cytokines that could affect CD4 priming, including IL-4, we were unable to distinguish a role for cytokines that are secreted by B cells. However, B cell costimulation via the OX40L/OX40 pathway that has been implicated in CD4 cell expansion, survival, and Th2 development was required. Th2 but not Th1 responses were impaired in OX40L-deficient recipients and normal responses were restored with OX40L sufficient B cells. The results suggest that without engagement of OX40L on B cells, CD4 cell responses to many protein Ag would be dominated by Th1 cytokines. These data have important implications for strategies to achieve optimal priming of CD4 subsets.
Linton
Phyllis-Jean
PJ
The Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121, USA. lbradley@skcc.org
Bautista
Beverly
B
Biederman
Elana
E
Bradley
Evan S
ES
Harbertson
Judith
J
Kondrack
Robyn M
RM
Padrick
Ryan C
RC
Bradley
Linda M
LM
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D001402:B-Lymphocytes / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis*; D018793:Interleukin-13 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053278:OX40 Ligand; D018418:Th2 Cells / Q000276:immunology*; D048069:Tumor Necrosis Factors
D016207:Cytokines; D018793:Interleukin-13; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D015847:Interleukin-4