T follicular helper cells (TFH) are a subset of CD4 T cells that reside almost exclusively in the lymph nodes, where they specialize in helping B cells generate antibodies. In a testament to the complexity and difficulty of studying the immune system, TFH were only identified as a discrete subset of CD4 T cells at the turn of the millennium. Since that time, several features that define TFH have been described, including high levels of the chemokine receptor CXCR5, expression of the PD-1 molecule, secretion of the cytokine IL-21, and upregulation of the Bcl-6 gene. Studies have also found TFH to be important for driving the process of affinity maturation (wherein B cells producing antibodies with increased affinity for their antigen target are progressively generated and selected), and for supporting the development of long-lived memory B cells.
Because TFH are relatively new on the scene, very little is known about how they are affected by HIV infection. A few months ago in the Journal of Clinical Investigation, two research groups published studies shedding light on this question. Madelene Lindqvist and colleagues looked at TFH in people with HIV and found they were significantly expanded in lymph nodes, with a major contribution from HIV-specific TFH (predominantly targeting the Gag protein). TFH levels were approximately tenfold higher in HIV-positive individuals compared to HIV-negative controls. Although high viral load was associated with around double the levels of TFH compared to undetectable viremia on ART, there was no direct correlation between viral load levels and TFH numbers. Notably, the extent of TFH expansion correlated with hypersecretion of antibodies by B cells, strongly suggesting that dysregulation of TFH contributes to B-cell dysfunction and hypergammaglobulinemia in people with HIV; these features of the infection were first reported in the early 1980s, but the underlying mechanisms have been unclear. Constantinos Petrovas and colleagues report broadly similar findings from the SIV/macaque model, additionally providing evidence that TFH are susceptible to infection.
In an accompanying commentary, TFH expert Carola Vinuesa highlights a number of important questions pertaining to this CD4 T-cell subset in HIV infection. Firstly, it has become apparent that several of the rare antibodies capable of broad neutralizing activity against multiple HIV isolates have undergone an unusual degree of affinity maturation, suggesting that interactions between TFH and B cells were essential in supporting their development; a better understanding of how this occurs could prove essential to designing an efficacious vaccine. The other side of this equation is that most individuals with HIV fail to generate effective neutralizing antibodies, and it will also be important to learn how TFH dysregulation contributes to this failure. From the standpoint of cure research, Vinuesa notes that these studies imply that TFH could contribute significantly to the persistent reservoir of HIV-infected cells and may therefore require specific targeting by reservoir-eliminating strategies.
Several webcasts of scientific talks relating to TFH and HIV are available free online. At CROI in March 2012, Carola Vinuesa provided an introductory overview and Madelene Lindqvist and Constantinos Petrovas presented some of the results described in these papers. In September at AIDS Vaccine 2012, Hendrick Streeck discussed the latest findings from his laboratory and Rick Koup offered a perspective on TFH and vaccines.
Symposium: Ontogeny of a Protective Immune Response to HIV (3rd presentation in session)
Follicular Helper and Regulatory T Cells Control the Quality of Antibody Responses
Carola Vinuesa, John Curtin Sch of Med Res, Australian Natl Univ, Canberra, Australia
Oral Abstract: Immune, Cellular, and Viral Factors Influencing HIV–Host Interplay (5th and 6th presentations in session)
SIV Infection Affects the Function, but not Survival, of Follicular T Helper Cells in Rhesus Macaques
Constantinos Petrovas, Vaccine Res Ctr, NIAID, NIH, Bethesda, MD, US
HIV-specific T Follicular Helper Cell Responses in Chronically Infected Individuals
Madelene Lindqvist, Ragon Inst of MGH, MIT, and Harvard, Boston, MA, US
T Follicular Helper Cells in HIV Infection
Hendrik Streeck, Ragon Institute of MGH, MIT, and Harvard, Boston, MA, US
Follicular T helper cells in vaccination and lentivirus pathogenesis
Richard A. Koup, Vaccine Research Center, Bethesda, MD, US
Journal of Clinical Investigation abstracts:
Published in Volume 122, Issue 9 (September 4, 2012)
J Clin Invest. 2012;122(9):3271–3280. doi:10.1172/JCI64314.
Research Article
Expansion of HIV-specific T follicular helper cells in chronic HIV infection
Madelene Lindqvist1, Jan van Lunzen2, Damien Z. Soghoian1, Bjorn D. Kuhl1, Srinika Ranasinghe1, Gregory Kranias1, Michael D. Flanders1, Samuel Cutler1, Naomi Yudanin3, Matthias I. Muller1, Isaiah Davis1, Donna Farber3, Philip Hartjen2, Friedrich Haag4, Galit Alter1, Julian Schulze zur Wiesch2 and Hendrik Streeck1
1Ragon Institute of MGH, MIT, and Harvard Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2Infectious Diseases Unit, University Medical Center Eppendorf, Hamburg, Germany.
3Columbia Center for Translational Immunology, Columbia University, New York, New York, USA.
4Department of Immunology, University Medical Center Eppendorf, Hamburg, Germany.
Authorship note: Madelene Lindqvist, Jan van Lunzen, and Hendrik Streeck contributed equally to this work.
HIV targets CD4 T cells, which are required for the induction of high-affinity antibody responses and the formation of long-lived B cell memory. The depletion of antigen-specific CD4 T cells during HIV infection is therefore believed to impede the development of protective B cell immunity. Although several different HIV-related B cell dysfunctions have been described, the role of CD4 T follicular helper (TFH) cells in HIV infection remains unknown. Here, we assessed HIV-specific TFH responses in the lymph nodes of treatment-naive and antiretroviral-treated HIV-infected individuals. Strikingly, both the bulk TFH and HIV-specific TFH cell populations were significantly expanded in chronic HIV infection and were highly associated with viremia. In particular, GAG-specific TFH cells were detected at significantly higher levels in the lymph nodes compared with those of GP120-specific TFH cells and showed preferential secretion of the helper cytokine IL-21. In addition, TFH cell expansion was associated with an increase of germinal center B cells and plasma cells as well as IgG1 hypersecretion. Thus, our study suggests that high levels of HIV viremia drive the expansion of TFH cells, which in turn leads to perturbations of B cell differentiation, resulting in dysregulated antibody production.
Published in Volume 122, Issue 9 (September 4, 2012)
J Clin Invest. 2012;122(9):3281–3294. doi:10.1172/JCI63039.
Research Article
CD4 T follicular helper cell dynamics during SIV infection
Constantinos Petrovas1, Takuya Yamamoto1, Michael Y. Gerner2, Kristin L. Boswell1, Kaska Wloka1, Emily C. Smith1, David R. Ambrozak1, Netanya G. Sandler3, Katherina J. Timmer3, Xiaoyong Sun4, Li Pan4, Amanda Poholek2, Srinivas S. Rao5, Jason M. Brenchley6, S. Munir Alam7, Georgia D. Tomaras7, Mario Roederer8, Daniel C. Douek3, Robert A. Seder9, Ronald N. Germain2, Elias K. Haddad4 and Richard A. Koup1
1Immunology Laboratory, Vaccine Research Center,
2Laboratory of Systems Biology, Lymphocyte Biology Section, and
3Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
4VGTI Florida, Port St. Lucie, Florida, USA.
5Laboratory Animal Medicine, Vaccine Research Center, and
6Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA.
7Duke Human Vaccine Institute, Duke University Medical School, Durham, North Carolina, USA.
8ImmunoTechnology Section and
9Cellular Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA.
CD4 T follicular helper (TFH) cells interact with and stimulate the generation of antigen-specific B cells. TFH cell interaction with B cells correlates with production of SIV-specific immunoglobulins. However, the fate of TFH cells and their participation in SIV-induced antibody production is not well understood. We investigated the phenotype, function, location, and molecular signature of TFH cells in rhesus macaques. Similar to their human counterparts, TFH cells in rhesus macaques represented a heterogeneous population with respect to cytokine function. In a highly differentiated subpopulation of TFH cells, characterized by CD150lo expression, production of Th1 cytokines was compromised while IL-4 production was augmented, and cells exhibited decreased survival, cycling, and trafficking capacity. TFH cells exhibited a distinct gene profile that was markedly altered by SIV infection. TFH cells were infected by SIV; yet, in some animals, these cells actually accumulated during chronic SIV infection. Generalized immune activation and increased IL-6 production helped drive TFH differentiation during SIV infection. Accumulation of TFH cells was associated with increased frequency of activated germinal center B cells and SIV-specific antibodies. Therefore, chronic SIV does not disturb the ability of TFH cells to help B cell maturation and production of SIV-specific immunoglobulins.
Published in Volume 122, Issue 9 (September 4, 2012)
J Clin Invest. 2012;122(9):3059–3062. doi:10.1172/JCI65175.
Commentary
HIV and T follicular helper cells: a dangerous relationship
Carola G. Vinuesa
Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
HIV infection leads to progressive destruction of infected CD4 T cells, hypergammaglobulinemia, and loss of memory B cells. Germinal centers, which are key to memory B cell formation and protective antibody responses, are major HIV reservoirs in which the virus replicates within T follicular helper (TFH) cells. In this issue of the JCI, the Koup and Streeck groups report that chronic SIV/HIV infection promotes TFH cell accumulation, which may drive B cell dysregulation. Their discoveries suggest that HIV harnesses TFH cells to evade the antibody response.
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