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Cross-Presentation of Male Seminal Fluid Antigens Elicits T Cell Activation to Initiate the Female Immune Response to Pregnancy¹

Lachlan M. Moldenhauer^*, Kerrilyn R. Diener^,, Dougal M. Thring^,, Michael P. Brown^,, John D. Hayball^,, and Sarah A. Robertson^2,*

^* Research Centre for Reproductive Health, School of Paediatric and Reproductive Health, University of Adelaide, Adelaide, Australia; Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia; Experimental Therapeutics Laboratory, Hanson Institute, Adelaide, Australia; and School of Medicine, University of Adelaide, Adelaide, Australia

The events that generate T cell-mediated immune tolerance in early pregnancy are ill-defined. To investigate the significance of seminal fluid Ags in activating maternal T cells, and define the underlying Ag presentation pathways, OVA-specific T cells were adoptively transferred to female mice inseminated by males ubiquitously expressing membrane-bound OVA. OVA-reactive CD8⁺ OT-I and CD4⁺ OT-II T cells transferred to mated recipients expressed activation markers CD25 and CD69 and proliferated vigorously in the para-aortic lymph nodes, but not in distal lymph nodes or spleen, and OT-I T cells expressed IFN- and IL-2. In contrast, OT-I T cells transferred later in pregnancy or up to 10 days postpartum expressed CD25 and CD69 and proliferated in all peripheral lymphoid tissues examined. OVA Ag was present predominantly in the plasma fraction of seminal fluid, and seminal plasma, but not sperm, was necessary for T cell proliferation. Female H-2K^b bone marrow-derived cells expressing TAP were essential for OT-I T cell proliferation, but responses were not elicited by OVA Ag presented by paternal MHC in seminal fluid or associated with placental cells. This study shows that at conception, seminal fluid drives activation and expansion of paternal Ag-reactive CD4⁺ and CD8⁺ T cell populations, and female APCs have an essential role in cross-presenting Ag to CD8⁺ T cells via a TAP-dependent pathway. Delivery of paternal Ags and immune-deviating cytokines by seminal fluid at conception may activate Ag-dependent CD4⁺ and CD8⁺ regulatory T cells mediating tolerance of pregnancy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by project and fellowship grants from the National Health and Medical Research Council (Australia).

² Address correspondence and reprint requests to Dr. Sarah A. Robertson, Research Centre for Reproductive Health, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005 Australia. E-mail address: sarah.robertson{at}adelaide.edu.au

³ Abbreviations used in this paper: Treg, T regulatory; DC, dendritic cell; ER, endoplasmic reticulum; LN, lymph node; pc, postcoitum; PI, proliferation index; pp, postpartum; SVX, surgical excision of the seminal vesicle gland.