TRegs (JCI)Our bodies are crammed with millions of tiny time bombs: lymphocytes that could begin to attack our own bodies, causing lethal autoimmune disease. Traditionally, it was said that these self-reactive lymphocytes were rare, because they were eliminated during their development and were never allowed to reach maturity. But it’s been known for quite a few years now that that’s not entirely true. The vast majority of self-reactive T cells may, indeed, be destroyed in the thymus, but by no means all. (Something like a couple million T cells leave a happy, functioning thymus every day. If central tolerance is 99.999% perfect, then 10 self-reactive T cells will enter the system every single day — and it only takes a couple of T cells to initiate a lethal disease.)

Why don’t we all die as infants of autoimmune attack, if circulating self-reactive T cells are so (relatively) common? As with just about everything in our body, there are redundant systems. For autoimmunity, the next line of defense is the regulatory T cell (TReg).

TRegs were identified as a phenomenon long ago, in the 1960s and 1970s; but the concept abruptly fell out of favor in 1984 (for fascinating and rather embarrassing reasons I talked about here), and it wasn’t until the new millennium that immunologists really returned to the field (first firmly changing the name from “suppressor T cells” to “TRegs” to keep their feet out of the muck), and the field really exploded 5 or 6 years ago.

TRegs have proved more important and powerful than just about anybody would have believed ten years ago. Even very powerful immune responses can be controlled by TRegs; strong TReg responses can actually allow a complete “take” of an organ transplant, for example (I mentioned some examples here).

 TRegs infiltrate tumor
Regulatory t cells infiltrate tumor tissue

As well as transplants, being able to turn on TRegs has potential for lots of other diseases. Autoimmunity, obviously, could be controlled this way; but also, less obviously, it’s possible that some virus diseases might benefit from a TReg response. HIV infection, for example, is exacerbated when T cells are activated, and monkeys with SIV are resistant to disease when their T cells are less reactive (see here and here); could a controlled TReg response reduce the harmful activation associated with HIV? It may seem counterintuitive to try to treat a viral disease by reducing immunity, but there is some precedent. Rodents infected with hantaviruses develop a TReg response and don’t have much disease (see here), while humans react with a more conventional immune response and have severe disease. And recently, it was shown that elite suppressors of HIV may have an exceptionally strong TReg response.1

Conversely, there are lots of instances where we’d like to turn off TRegs, in a controlled way. Tumors are often associated with TRegs, which very likely prevent a cleansing immune response to the tumor (discussed here). And the well-known observation that the elderly often have poor immunity against various pathogens is at least partly because TRegs build up over time.

This is a very fast-moving field, and there are a several recent papers that show exciting advances. One is a huge basic step forward, and I’ll talk about that later. The others2 are technical advances, developing new techniques (that are much less cumbersome and finicky than some of the previous approaches) to generate large numbers of TRegs in a controlled way. The obvious use for this is in transplants:

The ex vivo expansion protocol that we describe will very likely increase the success of clinical Treg-based immunotherapy, and will help to induce tolerance to selected antigens, while minimizing general immune suppression. This approach is of particular interest for recipients of HLA mismatched transplants.3

Controlled TRegs have been a holy grail of transplant biology for years, and it’s exciting to see that we may finally be entering an era when TRegs can be produced and used as tools.

  1. Preservation of FoxP3+ regulatory T cells in the peripheral blood of human immunodeficiency virus type 1-infected elite suppressors correlates with low CD4+ T-cell activation.
    Chase AJ, Yang HC, Zhang H, Blankson JN, Siliciano RF
    J Virol 2008 Sep 82(17):8307-15[]
  2. Including, but not limited to:
    W. Tu, Y.-L. Lau, J. Zheng, Y. Liu, P.-L. Chan, H. Mao, K. Dionis, P. Schneider, D. B. Lewis (2008). Efficient generation of human alloantigen-specific CD4+ regulatory T cells from naive precursors by CD40-activated B cells Blood, 112 (6), 2554-2562 DOI: 10.1182/blood-2008-04-152041

    In Vitro Expanded Human CD4+CD25+ Regulatory T Cells are Potent Suppressors of T-Cell-Mediated Xenogeneic Responses. Wu, Jingjing; Yi, Shounan; Ouyang, Li; Jimenez, Elvira; Simond, Denbigh; Wang, Wei; Wang, Yiping; Hawthorne, Wayne J.; O’Connell, Philip J. Transplantation Volume 85(12), 27 June 2008, pp 1841-1848.

    Jorieke H. Peters, Luuk B. Hilbrands, Hans J. P. M. Koenen, Irma Joosten (2008). Ex Vivo Generation of Human Alloantigen-Specific Regulatory T Cells from CD4posCD25high T Cells for Immunotherapy PLoS ONE, 3 (5) DOI: 10.1371/journal.pone.0002233

    and a review in Piotr Trzonkowski, Magdalena Szary?ska, Jolanta My?liwska, Andrzej My?liwski (2008). Ex vivo expansion of CD4+CD25+ T regulatory cells for immunosuppressive therapy
    Cytometry Part A, 9999A DOI: 10.1002/cyto.a.20659

  3. Jorieke H. Peters, Luuk B. Hilbrands, Hans J. P. M. Koenen, Irma Joosten (2008). Ex Vivo Generation of Human Alloantigen-Specific Regulatory T Cells from CD4posCD25high T Cells for Immunotherapy PLoS ONE, 3 (5) DOI: 10.1371/journal.pone.0002233[]