November 26, 2012
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 10-fold 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.
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.
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