Interaction of programmed death-1 and programmed death-1 ligand-1 contributes to testicular immune privilege.
BACKGROUND
Immune responses are tempered in immunologically privileged sites including the testis. Previous studies have shown that islet transplantation in the testis significantly prolongs islet allograft survival. However, mechanisms underlying testicular immune privilege and intratesticular allograft survival remain unclear.


METHODS
Allogeneic murine islets were transplanted in the testis. Programmed death-1 ligand-1 (PD-L1) expression was detected by immunohistochemstry and real-time polymerase chain reaction. Infiltrating T-cell proliferation was measured by bromodeoxyuridine uptakes, whereas their apoptosis was quantified by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling methods. Transgenic T cells were used to track allospecific memory T-cell generation.


RESULTS
We found that programmed death-1 (PD-1):PD-L1 negative costimulation is essential for prolonged survival of intratesticular islet allografts, as blocking PD-L1 or PD-1, but not PD-L2 and cytotoxic T-lymphocyte antigen 4, abrogated long-term survival of intratesticular islet allografts. As controls, blocking PD-1 or PD-L1 did not significantly accelerate the acute rejection of islet allografts transplanted under the renal capsule, a conventional islet-grafting site. We also found for the first time that PD-L1 is constitutively expressed mainly by spermatocytes and spermatids in seminiferous tubules of the testis. Moreover, infiltrating T cells underwent less vigorous proliferation but faster apoptosis in the testis than in the kidney. Blocking PD-1:PD-L1 costimulation largely abolished the suppression of T-cell proliferation and acceleration of T-cell apoptosis. Importantly, testicular immune privilege significantly suppressed the generation and proliferation of donor-specific memory CD8 T cells.


CONCLUSIONS
The constitutive expression of PD-L1 in the testis is an important mechanism underlying testicular immune privilege and long-term survival of intratesticular islet allografts.
Cheng
Xuyang
X
Center for Biomedical Research, University of Texas Health Science Center, Tyler, TX 75708, USA.
Dai
Hehua
H
Wan
Ni
N
Moore
Yolonda
Y
Vankayalapati
Ramakrishna
R
Dai
Zhenhua
Z
D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology*; D060890:B7-H1 Antigen; D017931:DNA Primers; D018398:Homeodomain Proteins / Q000235:genetics; D007150:Immunohistochemistry; D007156:Immunologic Memory; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D013737:Testis / Q000276:immunology*; D016042:Transplantation, Heterotopic / Q000379:methods; D014184:Transplantation, Homologous / Q000276:immunology
D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D017931:DNA Primers; D018398:Homeodomain Proteins; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D034741:RNA, Small Interfering; C064658:RAG-1 protein