Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Molecular mimicry wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Atherosclerosis wikipedia , lookup
Immune system wikipedia , lookup
Lymphopoiesis wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Adaptive immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne HIV persistence in the testis? Does HIV persist in the testis? Why should we care? • • Transmission through seminal plasma? ? Reservoir during cART? Is the testis a sanctuary for HIV? Possible mechanisms for HIV persistence in the testis: • Blood testis barrier? • Testicular immune privilege? ? Cells of the testis Interstitium Seminiferous tubule Lumen lymphatic vessel blood vessel Cells of the testis Interstitium Seminiferous tubule Lumen Spermatids lymphatic vessel blood vessel Spermatocytes Spermatogonia Cells of the testis Interstitium Seminiferous tubule Sertoli cells Lumen lymphatic vessel blood vessel Cells of the testis Interstitium Seminiferous tubule Sertoli cells Blood-testis barrier Lumen Pgp lymphatic vessel blood vessel Cells of the testis Interstitium Seminiferous tubule Sertoli cells Blood-testis barrier Lumen Pgp Leukocytes: macrophages T cells lymphatic vessel blood vessel Leydig cells Is the testis a sanctuary for HIV? Possible mechanisms for HIV persistence in the testis: • Blood testis barrier? • Testicular immune privilege? ? Is the testis a sanctuary for HIV? Possible mechanisms for HIV persistence in the testis: • Blood testis barrier? • Testicular immune privilege? • • Suppression of innate and acquired immune responses in the testis of rodents Predicted to protect immunogenic spermatids from immune responses and inflammation ? Pigtailed macaque model for HIV infection SIV infects the pigtailed macaque testis Shehu-Xhilaga et al Retrovirology, 2007 Aims • • • Are immune responses suppressed in the macaque testis? How does SIV infection affect the testis? Do testicular CD8 T cells respond to SIV infection? SIV infection of pigtailed macaques Testes and blood taken from: • 7 uninfected macaques • 4 macaques infected with SIVmac239 • • 10 weeks 24 to 30 weeks Is there immunosuppression in the macaque testis? unstimulated mitogen stimulation Is there immunosuppression in the macaque testis? unstimulated mitogen stimulation Wilcoxon Signed Rank test • T cell responses in the testis are lower than in the blood Aims • • • Are immune responses suppressed in the macaque testis? How does SIV infection affect the testis? Do testicular CD8 T cells respond to SIV infection? SIV damages the macaques testis uninfected SIV week 10 VERALL T and B.jo Layout: fig for poster SIV alters testis leukocyte populations uninfected testis CD3+ 105 104 40.2 SIV week 10 CD3+ 10 5 10 4 10 CD8 CD8 83 103 3 41 /7/14 1:09 PM 3.77 0 0 0 10 3 10 CD4 4 10 5 0 10 3 10 4 10 5 CD4 Page 1 of 1 (FlowJo v9.7.5) VERALL T and B.jo Layout: fig for poster SIV alters testis leukocyte populations uninfected testis CD3+ CD4 cells in the testis and blood SIV week 10 CD3+ 103 41 /7/14 1:09 PM 3.77 0 10 5 0 10 3 10 4 10 5 CD4 0 k3 0 k1 w 4 CD8 cells in the testis and blood 100 blood WB testis testis 80 60 40 20 0 Page 1 of 1 0 10 CD4 w 3 k3 10 w 0 10 0 % CD8 out of CD3 cells 0 20 0 3 30 k1 10 CD8 CD8 83 40 w 10 4 WB blood testis testis un in fe ct ed 40.2 5 un in fe ct ed 104 10 % CD4 out of CD3 cells 50 105 (FlowJo v9.7.5) VERALL T and B.jo Layout: fig for poster SIV alters testis leukocyte populations uninfected testis CD3+ CD4 cells in the testis and blood SIV week 10 CD3+ 103 41 3.77 0 0 10 3 10 4 10 5 10 0 CD4 10 3 10 4 10 5 CD4 0 0 k3 0 20 w 3 30 0 10 CD8 CD8 83 40 k1 10 4 WB blood testis testis w 40.2 5 un in fe ct ed 104 10 % CD4 out of CD3 cells 50 105 CD8 cells in the testis and blood /7/14 1:09 PM 20 k3 0 0 w Shift towards effector memory and Page 1 of 1 away from central memory 40 0 • 60 k1 Influx of CD8 T cells 80 w Loss of CD4 T cells blood WB testis testis un in fe ct ed • • 100 % CD8 out of CD3 cells SIV infection lead to: (FlowJo v9.7.5) Aims • • • Are immune responses suppressed in the macaque testis? How does SIV infection affect the testis? Do testicular CD8 T cells respond to SIV infection? Are there CD8 T cell responses in the SIV-infected testis? mer.jo uninfected testis CD8+ 5 10 0.0354 104 10 tetramer KP9-ManeA*084 KP9 tetramer tetramer KP9-ManeA*084 KP9 tetramer 10 SIV week 10 CD8+ 5 3.93 104 3 10 102 3 102 0 0 10 3 CD8 10 4 10 5 0 0 10 3 CD8 10 4 10 5 Are there CD8 T cell responses in the SIV-infected testis? mer.jo 102 0 0 10 3 CD8 • 10 4 10 5 2 0 0 0 10 3 10 4 10 5 0 102 3 4 k3 10 testis testis w 3 blood WB 0 10 3.93 104 6 k1 0.0354 104 5 w 10 SIV-specific CD8 T cells in testis and blood KP9 tetramer positive cells in blood and testis % KP9+ out of CD8+ cells 5 tetramer KP9-ManeA*084 KP9 tetramer tetramer KP9-ManeA*084 KP9 tetramer 10 SIV week 10 CD8+ un in fe ct ed uninfected testis CD8+ CD8 SIV-specific CD8 T cells were detected in the testis SIV inhibits CD8 T cell cytokine production layout for poster SIV wk 10 testis CD8+ 10 5 SIV wk 10 blood CD8+ 0.0831 0 10 0.365 1.99 104 TNF TNF 104 5 10 3 3 10 0 0 97.7 2.2 0 3 10 10 4 10 91.8 5 5.88 0 IFN 3 10 10 4 10 5 IFN Page 1 of 1 (FlowJo v9.7.5) SIV inhibits CD8 T cell cytokine production layout for poster 3 10 0 0 97.7 2.2 0 3 10 10 4 10 91.8 5 0 IFN • 5.88 3 10 10 IFN 4 10 5 WB blood testis testis 10 5 0 0 3 15 k3 1.99 w 10 0.365 104 TNF TNF 104 5 10 0 0 k1 0.0831 w 5 un in fe ct ed 10 Cytokineproduction productionafter by CD8 cells stimulation Cytokine mitogen SIV wk 10 blood CD8+ % CD8+ producing IFNg or TNF SIV wk 10 testis CD8+ SIV infection inhibited cytokine production by CD8 T cells in response to mitogens Page 1 of 1 (FlowJo v9.7.5) Summary • T cell responses to mitogens are relatively low in the macaque testis Evidence for immune privilege in the primate testis • SIV infection affects the macaque testis: • Damage to the testis architecture • Influx of effector memory CD8 T cells • Loss of CD4 T cells Summary • • SIV-specific CD8 T cells were detected in the testis However cytokine production in response to mitogens was inhibited by SIV infection Immunosuppression in the macaque testis reduces the ability of CD8 T cells to respond to infection, making the testis vulnerable to persistent SIV infection and damage. • Testicular immune privilege Acknowledgements Kent Lab, Doherty Institute University of Melbourne Stephen Kent Rob De Rose Sarah Lloyd Vinca Alcantara Thakshila Amarasena Marit Kramski Shayarana Gooneratne Hyon-Xhi Tan Monash University Mark Hedger Dept of Obstetrics and Gynaecology, University of Melbourne Jane Girling CSIRO AAHL Geelong Megan Schepers Lisa Reid