TReg (Artist's impression from BioLegend)After the “suppressor T cell” debacle of the 1980s, there was an embarrassed pause for a few years before people dipped their toes back into the suppressor T cell water; but the underlying phenomenon itself is a very strong and important one, and by the late 1990s and early 2000s researchers were again studying the cells, renaming them “regulatory T cells” (TRegs) in the process. Since the phenomenon is so strong, the field quickly exploded (from two papers mentioning TRegs in 2000, to 780 this year). We now know where TRegs are made and, mostly, how they’re made; we know what they look like and which cells they talk with; we know of various ways to make them in the lab; we know diseases where they’re overactive, and diseases where they’re underactive.  I’ve talked about these things quite a bit here.  

We didn’t know, though, how they actually work. Do they act directly on their target T cells, or via intermediaries? Do they have to contact their targets, or can they act at a distance? What molecules deliver their “regulatory” signals, and what molecules receive the signal? Well, we still don’t really know the answers to most of those questions, but a paper last month1 brought the answers a lot closer with evidence that CTLA4 is essential for TRegs to have their regulatory effect.

TRegs in skin
TRegs in normal skin

This isn’t a new idea; it was first put forward in one of the very early TReg papers, way back in 20002. The difference is that the earlier papers couldn’t cleanly distinguish TReg-specific effects of CTLA4 from its myriad other effects. CTLA4 is a very broad-acting molecule with lots of immunosuppressive (or if you prefer, immunoregulatory) activities. In the present paper, Wing et al managed to eliminate CTLA4 specifically from TReg cells, leaving its other activities intact. These TReg-specific knockouts still developed the horrible, fatal autoimmune diseases characteristic of TReg deficiencies.

So CTLA4 is essential for TReg function. This is especially interesting because there’s a lot of clinical interest in CTLA4; for example, blocking CTLA4 has been effective in generating (or regenerating) immunity to cancers, at least in experimental models. The rationale for this has been because signaling through CTLA4 on “conventional” (that is, effector, as opposed to regulatory) T cells reduces or blocks their activity;3 but now this is directly linked to TReg activity as well.

The link between TRegs, CTLA4, and tumor immunity was really emphasized in the Wing et al paper. In one experiment, they demonstrated that mice with normal TRegs were not able to reject a tumor (“All recipients of FIC splenocytes died of tumor progression within a month“), whereas mice with the knockout TRegs (that is, TRegs lacking CTLA4) were able to control it (“In contrast, recipients of CKO splenocytes halted the tumor growth, with the majority surviving the 6-week observation period, during which 60% of them completely rejected the tumor“).

Obviously, you don’t want to eliminate TReg function willy-nilly even in cancer patients; remember that these mice died of autoimmune disease when they were a couple of months old. But if there’s a way of localizing CTLA4 blockade so that the tumor-specific TRegs alone are affected, this could be very interesting.

  1. K. Wing, Y. Onishi, P. Prieto-Martin, T. Yamaguchi, M. Miyara, Z. Fehervari, T. Nomura, S. Sakaguchi (2008). CTLA-4 Control over Foxp3+ Regulatory T Cell Function Science, 322 (5899), 271-275 DOI: 10.1126/science.1160062

    Also see the commentary by Ethan Shevach:
    E. M. Shevach (2008). IMMUNOLOGY: Regulating Suppression Science, 322 (5899), 202-203 DOI: 10.1126/science.1164872[]

  2. Cytotoxic T Lymphocyte–Associated Antigen 4 Plays an Essential Role in the Function of Cd25+Cd4+ Regulatory Cells That Control Intestinal Inflammation.  S. Read, V. Malmstrom, F. Powrie, J. Exp. Med. 192, 295 (2000).[]
  3. For a review, see:
    Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Karl S Peggs, Sergio A Quezada, Alan J Korman and James P Allison Curr Opin Immunol. 2006 Apr;18(2):206-13. doi:10.1016/j.coi.2006.01.011[]