Frontiers in Immunology (Sep 2018)
High-Frequency, Functional HIV-Specific T-Follicular Helper and Regulatory Cells Are Present Within Germinal Centers in Children but Not Adults
- Julia Roider,
- Julia Roider,
- Julia Roider,
- Julia Roider,
- Takashi Maehara,
- Abigail Ngoepe,
- Duran Ramsuran,
- Maximilian Muenchhoff,
- Maximilian Muenchhoff,
- Emily Adland,
- Toby Aicher,
- Toby Aicher,
- Toby Aicher,
- Samuel W. Kazer,
- Samuel W. Kazer,
- Samuel W. Kazer,
- Pieter Jooste,
- Farina Karim,
- Warren Kuhn,
- Alex K. Shalek,
- Alex K. Shalek,
- Alex K. Shalek,
- Thumbi Ndung'u,
- Thumbi Ndung'u,
- Thumbi Ndung'u,
- Thumbi Ndung'u,
- Thumbi Ndung'u,
- Lynn Morris,
- Lynn Morris,
- Lynn Morris,
- Penny L. Moore,
- Penny L. Moore,
- Penny L. Moore,
- Shiv Pillai,
- Henrik Kløverpris,
- Henrik Kløverpris,
- Henrik Kløverpris,
- Philip Goulder,
- Philip Goulder,
- Alasdair Leslie,
- Alasdair Leslie
Affiliations
- Julia Roider
- Africa Health Research Institute, University of KwaZulu-Natal, Durban, South Africa
- Julia Roider
- Department of Paediatrics, Peter Medawar Building for Pathogen Research, Oxford University, Oxford, United Kingdom
- Julia Roider
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
- Julia Roider
- Department of Infectious Diseases, Medizinische Klinik IV, Ludwig-Maximilians-University Munich, Munich, Germany
- Takashi Maehara
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States
- Abigail Ngoepe
- Africa Health Research Institute, University of KwaZulu-Natal, Durban, South Africa
- Duran Ramsuran
- Africa Health Research Institute, University of KwaZulu-Natal, Durban, South Africa
- Maximilian Muenchhoff
- Department of Virology, Max von Pettenkofer Institute, Ludwig-Maximilians-University Munich, Munich, Germany
- Maximilian Muenchhoff
- Partner Site Munich, German Center for Infection Research, Munich, Germany
- Emily Adland
- Department of Paediatrics, Peter Medawar Building for Pathogen Research, Oxford University, Oxford, United Kingdom
- Toby Aicher
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States
- Toby Aicher
- Department of Chemistry and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, United States
- Toby Aicher
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Samuel W. Kazer
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States
- Samuel W. Kazer
- Department of Chemistry and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, United States
- Samuel W. Kazer
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Pieter Jooste
- 0Paediatric Department, Kimberley Hospital, Kimberley, South Africa
- Farina Karim
- Africa Health Research Institute, University of KwaZulu-Natal, Durban, South Africa
- Warren Kuhn
- 1Department of Otorhinolaryngology, Stanger Hospital, KwaZulu-Natal, South Africa
- Alex K. Shalek
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States
- Alex K. Shalek
- Department of Chemistry and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, United States
- Alex K. Shalek
- Broad Institute of MIT and Harvard, Cambridge, MA, United States
- Thumbi Ndung'u
- Africa Health Research Institute, University of KwaZulu-Natal, Durban, South Africa
- Thumbi Ndung'u
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
- Thumbi Ndung'u
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States
- Thumbi Ndung'u
- 2Max Planck Institute for Infection Biology, Berlin, Germany
- Thumbi Ndung'u
- 3Department of Infection and Immunity, University College London, London, United Kingdom
- Lynn Morris
- 4Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa
- Lynn Morris
- 5Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Lynn Morris
- 6Center for the AIDS Programme of Research in South Africa, Durban, South Africa
- Penny L. Moore
- 4Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa
- Penny L. Moore
- 5Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Penny L. Moore
- 6Center for the AIDS Programme of Research in South Africa, Durban, South Africa
- Shiv Pillai
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States
- Henrik Kløverpris
- Africa Health Research Institute, University of KwaZulu-Natal, Durban, South Africa
- Henrik Kløverpris
- 3Department of Infection and Immunity, University College London, London, United Kingdom
- Henrik Kløverpris
- 7Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
- Philip Goulder
- Department of Paediatrics, Peter Medawar Building for Pathogen Research, Oxford University, Oxford, United Kingdom
- Philip Goulder
- HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
- Alasdair Leslie
- Africa Health Research Institute, University of KwaZulu-Natal, Durban, South Africa
- Alasdair Leslie
- 3Department of Infection and Immunity, University College London, London, United Kingdom
- DOI
- https://doi.org/10.3389/fimmu.2018.01975
- Journal volume & issue
-
Vol. 9
Abstract
Broadly neutralizing antibodies (bnAbs) against HIV-1 are an effective means of preventing transmission. To better understand the mechanisms by which HIV-specific bnAbs naturally develop, we investigated blood and lymphoid tissue in pediatric infection, since potent bnAbs develop with greater frequency in children than adults. As in adults, the frequency of circulating effector T-follicular helper cells (TFH) in HIV infected, treatment naïve children correlates with neutralization breadth. However, major differences between children and adults were also observed both in circulation, and in a small number of tonsil samples. In children, TFH cells are significantly more abundant, both in blood and in lymphoid tissue germinal centers, than in adults. Second, HIV-specific TFH cells are more frequent in pediatric than in adult lymphoid tissue and secrete the signature cytokine IL-21, which HIV-infected adults do not. Third, the enrichment of IL-21-secreting HIV-specific TFH in pediatric lymphoid tissue is accompanied by increased TFH regulation via more abundant regulatory follicular T-cells and HIV-specific CXCR5+ CD8 T-cells compared to adults. The relationship between regulation and neutralization breadth is also observed in the pediatric PBMC samples and correlates with neutralization breadth. Matching neutralization data from lymphoid tissue samples is not available. However, the distinction between infected children and adults in the magnitude, quality and regulation of HIV-specific TFH responses is consistent with the superior ability of children to develop high-frequency, potent bnAbs. These findings suggest the possibility that the optimal timing for next generation vaccine strategies designed to induce high-frequency, potent bnAbs to prevent HIV infection in adults would be in childhood.
Keywords
- pediatric HIV infection
- broadly neutralizing antibodies (bnAb)
- T-follicular helper cells (Tfh)
- T-follicular regulatory helper cells (Tfreg)
- follicular CD8 T-cells
- germinal center
