醫(yī)學(xué)免疫學(xué)課件：HIV感染對TFH細胞的影響

1、Impact of HIV Infectionon T Follicular Helper CellBackground of AIDS AIDS-related death toll of over 25 million HIV-1 more severe Highly active antiretroviral therapy (HAART) Stabilize the symptoms and viremia Not cure the patient or the symptoms Not prevent the spread Increasing viral resistance an

2、d side effects No vaccine today even after 30 years researchWhy no vaccines so far? HIV structure Highly mutable so that can evade the immune system Highly variable for HIV isolates and broad enough for vaccine Animal model Hard to stimulate antibodies in monkey Real differences between SIV and HIVD

3、iscovery of bNAb 1993 discovery of broadly neutralizing antibodies Bind to conserved part Can cover many HIV isolates 20-30% of HIV-1 infected people 2-4 years required Jon Cohen Science 2013;341:1168-1171Boom in bNAb publicationsWhy bNAb? T cellbased vaccines against HIV failed miserably Developed

4、improved techniquesData from pubmedProduction of AbFranco Pissaniand Hendrik Streeck Cell 2014;35 :278-286Follicular helper T cell (Tfh cell)Follicular helper T cellsCrotty S. Annu. Rev. Immunol. 2011;29 :621-630A. Differentiation TfrStphanie Graff-Dubois*, Angeline Rouers and Arnaud Moris. Front. I

5、mmunol. 2016(7).501-510B. Subsets of Tfh cells C. Regulation and control Crotty S. Annu. Rev. Immunol. 2011;29 :621-630ExamplesCostimulatory molecules: CD40L, ICOS, OX40Plasma cell formation: IL-21， IL-4Thus, important for GC formation, SHM, B cell differentiation, Ig CSRAs for HIVB. Significantly e

6、nriched in total HIV-specific CD4 T cells. Crotty S. Annu. Rev. Immunol. 2011;29 :621-630A. Tfh cells are significantly increased. Various hypotheses Tfh cells might present high proliferative or survival capacities Antigen persistence could drive CD4 T cells toward Tfh differentiation Regulatory ce

7、lls that control the Tfh/B cell crosstalk might be defective.Potential impact of HIV Impact on Tfh cell differentiation Impact on controlling factors Tfh dynamics during HIV Alteration of Tfh functionsImpact on Tfh cell differentiation HIV binds DC-SIGN to support Tfh polarization Teunis B. H. Geijt

8、enbeek etc. Cell, 2000. Vol. 100, 587597Impact on Tfh cell differentiation HIV binds DC-SIGN to support Tfh polarizationSonja I. Gringhuis1. etc. NATURE COMMUNICATIONS.2014, 587597Constantinos Petrovas。etc. J Clin Invest. 2012;122(9):32813294Impact on Tfh cell differentiation HIV help alternative“po

9、st effector”pathwayLucie Colineau。etc. PLoS ONE。2015。10（10） Alternative from memory CD4 T or effector helper T IL-7 downregulates the differentiation between Th1 and TfhIL7IL-7B. Impact on controlling factorsAnkita Chowdhury etc. J Immunol. 2015 October 1; 195(7): 32373247 Tfh cell homeostasis favor

10、s survival of high affinity B cell clones. Treg cell, Tfr cell, CD8 regulatory cell, Plasma cell Increased GC and T cell responses in the absence of TfrC. Tfh dynamics during HIVStphanie Graff-Dubois*, Angeline Rouers and Arnaud Moris. Front. Immunol. 2016(7).501-510 High susceptibility to HIV/SIV i

11、nfection and accumulation during infection Reduced in individuals that control HIV infection However, it is just the most of studies.C. Tfh dynamics during HIVYoshinori Fukazawa1, etc, Nat Med. 2015 February ; 21(2): 132139 The accessibility of CTL to GC is reducedC. Tfh dynamics during HIVHuanbin X

12、u, etc.J Immunol. 2015 November 1; 195(9): 43514357 GC drives Tfh cell expansion during HIV infectionD. Alteration of Tfh functionsG. VANHAM, etc. Clin Exp Immunol 1999; 117:335342 Provide B cell helper signals and to promote their differentiation The impact of HIV/SIV infection on the main signals

13、CD40L-CD40 interactions are required for GC reactionC. Alteration of Tfh functionsKristin L. Boswell, etcPLOS Pathogens. January 2014 | Volume 10 | Issue 1 ICOS by Tfh cells plays a major role in selection of high affinity B cellsC. Alteration of Tfh functionsKristin L. Boswell, etcPLOS Pathogens. J

14、anuary 2014 | Volume 10 | Issue 1 Tfh-secreted IL-21 induces B cell affinity maturationC. Alteration of Tfh functionsConstantinos Petrovas. etc. J Clin Invest. 2012;122(9):32813294 IL-4 confers anti-apoptotic properties to GC B cells IL-4 also participates to GC B cells selectionC. Alteration of Tfh

15、 functions SLAMF1 is required for IL-4 and IL-21 production by GC Tfh cells Detected a defective SLAMF1 gene expression in Tfh cell SLAMF1 OX40 OX40OX40L interaction is required for B cell differentiation In humans, mutations in OX40 gene lead to decreased proportion of circulating memory B cells bu

16、t do not impact the Ab responsesHIV-infected spleens exhibit defective expression of gene encoding OX40 in TfhTo sum upGCTfhBDCTfrCTLTh1IL-7HIVIL-27,IL-6CD40,ICOS,IL-21,IL-4,SLAMF1,OX40Conclusion Vaccine needs to remove the inhibition to B cells Early ART during infection limits Tfh reservoir Combin

17、ing HIV protease-sensitive toxin nanocapsules More research needs doing Reference 1.Miles, B., et al., Follicular regulatory T cells impair follicular T helper cells in HIV and SIV infection. Nature Communications, 2015. 6: p. 8608. 2.Hong, J.J., K. Chang and F. Villinger, The Dynamics of T and B Ce

18、lls in Lymph Node during Chronic HIV Infection: TFH and HIV, Unhappy Dance Partners? Frontiers in Immunology, 2016. 7. 3.Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target. 4.Phetsouphanh, C., Y. Xu and J. Zaunders, CD4 T Cells Mediate Both Positive and

19、Negative Regulation of the Immune Response to HIV Infection: Complex Role of T Follicular Helper Cells and Regulatory T Cells in Pathogenesis. Frontiers in Immunology, 2015. 5. 5.Zhang, Z., et al., Antiviral Therapy by HIV-1 Broadly Neutralizing and Inhibitory Antibodies. International Journal of Mo

20、lecular Sciences, 2016. 17(11): p. 1901. 6.Doria-Rose, N.A., et al., Frequency and Phenotype of Human Immunodeficiency Virus Envelope-Specific B Cells from Patients with Broadly Cross-Neutralizing Antibodies. Journal of Virology, 2008. 83(1): p. 188-199. 7.Bound for Glory. 8.van Gils, M.J., et al.,

21、Prevalence of cross-reactive HIV-1-neutralizing activity in HIV-1-infected patients with rapid or slow disease progression. AIDS, 2009. 23(18): p. 2405-2414. 9.Perreau, M., et al., Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. T

22、he Journal of Experimental Medicine, 2013. 210(1): p. 143-156.10.Geijtenbeek, T.B., et al., DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell, 2000. 100(5): p. 587-97.11.Gringhuis, S.I., et al., Fucose-based PAMPs prime dendritic cells for follic

23、ular T helper cell polarization via DC-SIGN-dependent IL-27 production. Nature Communications, 2014. 5: p. 5074.Reference12.Petrovas, C., et al., CD4 T follicular helper cell dynamics during SIV infection. Journal of Clinical Investigation, 2012. 122(9): p. 3281-3294.13.Colineau, L., et al., HIV-Inf

24、ected Spleens Present Altered Follicular Helper T Cell (Tfh) Subsets and Skewed B Cell Maturation. PLOS ONE, 2015. 10(10): p. e0140978.14.Chowdhury, A., et al., Decreased T Follicular Regulatory Cell/T Follicular Helper Cell (TFH) in Simian Immunodeficiency VirusInfected Rhesus Macaques May Contribu

25、te to Accumulation of TFH in Chronic Infection. The Journal of Immunology, 2015. 195(7): p. 3237-3247.15.Fukazawa, Y., et al., B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nature Medicine, 2015. 21(2): p. 132-139.16.Xu, H., et al., Persistent Simian Immunodeficiency Virus Infection Causes Ultimate Depletion of Follicular Th Cells in AIDS. The Journal of Immunology, 2015. 195(9): p. 4351-4357.17.Vanham, G., et al., Decreased CD40 ligand induction in CD4 T