Superfluous or misguided human immune responses may lead to harmful outcomes, as seen in autoimmune disease and allergy, but the immune system has evolved mechanisms to suppress these reactions. One of the key molecules engaged in such suppressive control is cytotoxic T lymphocyte antigen–4 [(CTLA-4); also called CD152] (1). The molecule is expressed by certain T cell subpopulations, and animals lacking CTLA-4 die prematurely from massive T cell proliferation and severe autoimmunity (2–4). It has not been clear how CTLA-4 negatively controls immune responses via these T cells, but on page 600 of this issue, Qureshi et al. (5) report a mechanism by which the molecule modulates the function of antigen-presenting cells (such as dendritic cells) to control immunological self-tolerance and homeostasis.
A naïve T cell (or Treg cell) expresses CTLA-4 when activated by signals from the T cell receptor (TCR) and coreceptor CD28. The receptors interact with antigen and CD80 (or CD86), respectively, on an antigen-presenting cell. The CTLA-4–CD80 (or CTLA-4–CD86) complex is endocytosed by the activated T cell, depleting CD80 (or CD86) from the antigen-presenting cell. The depleted cell cannot further activate the T cell or other T cells. MHC, major histocompatibility complex.
CREDIT: Y. HAMMOND/SCIENCE
Activation of a naïve T cell by antigenic stimulation requires two independent signals: one from the T cell receptor upon its association with antigen presented to it and the other from the costimulatory receptor CD28, both in the immunological synapse (the interface between an antigen-presenting cell and a T cell). CD28 and CTLA-4 are structurally homologous, and both bind to the same ligands (CD80 and CD86) expressed on the surface of antigen-presenting cells (1). Following stimulation by antigen, CTLA-4 expression is induced in activated T cells such as helper T cells (CD4 subclass, which enhances the activity of other immune cells) and cytotoxic T cells (CD8 subclass, which induces the death of target cells, such as cancer cells). CTLA-4 is also constitutively expressed by regulatory T (Treg) cells (a subpopulation of those that express CD4), which are specialized for immunosuppressive function (6).
For more than two decades, CTLA-4 has been considered a co-inhibitory receptor, transducing a negative signal into an activated T cell that attenuates T cell receptor and CD28 signals. In support of this idea, ligation of CTLA-4 molecules on activated T cells by specific antibody inhibits their production of interleukin-2, a major cytokine required for T cell proliferation, differentiation, and survival (7, 8). Yet, CTLA-4 may also have a “cell-extrinsic” function in immune suppression (4, 9). That is, CTLA-4 expressed by Treg cells and activated T cells dampens the expression of CD80 and CD86 by antigen-presenting cells.
Qureshi et al. demonstrate that when CTLA-4–expressing antigen-activated T cells are cultured with CD86-expressing dendritic cells, the former remove CTLA-4–bound CD86 molecules from the surface of the dendritic cells. T cells actively internalize the CTLA-4–CD86 complexes through endocytosis, and rapidly degrade CD86 molecules in the cytoplasm. The authors also show in vivo that, after administering antigen to normal animals, antigen-specific Treg cells predominantly endocytose CD86 from antigen-presenting cells, whereas CTLA-4–deficient Treg cells do not. CD80 seems to be similarly removed from the surface of antigen-presenting cells because it has a higher affinity for CTLA-4 than does CD86. Thus, depletion of CD80 or CD86 from antigen-presenting cells by CTLA-4–dependent trans-endocytosis, and the resulting inability of the antigen-presenting cell to provide T cells with costimulation through CD28, inhibits excessive activation of CTLA-4–expressing T cells and may also allow Treg cells to suppress the activation of other T cells recruited to the antigen-presenting cells (see the figure).
Yet, the findings of Qureshi et al. do not exclude other possible cell-extrinsic or cell-intrinsic functions of CTLA-4 suggested by the variant forms of the protein, including ligand-dependent and ligand-independent forms, as well as the soluble one (1). In addition to its role in trans-endocytosis, CTLA-4 may simply outcompete CD28 for binding to CD80 or CD86 in the immunological synapse because of its much higher binding affinity for the ligands and its increased expression upon T cell receptor stimulation (10). Soluble CTLA-4 might block CD80 and CD86 (1). The ligand-independent form may attenuate T cell activation by a cell-intrinsic mechanism (11). CTLA-4 may also transduce signals via CD80 and CD86 into antigen-presenting cells and induce their production of an immunosuppressive metabolite, repress the transcription of the genes encoding CD80 or CD86, or inhibit the production of inflammatory cytokines, although how T cells evoke these events in antigen-presenting cells via CTLA-4 remains obscure (12).
CTLA-4 is a key molecular target for enhancing or damping immune responses clinically. CTLA-4 blockade by specific monoclonal antibody evokes effective immune response to tumors, and blockade of CD80 or CD86 by a CTLA-4–immunoglobulin fusion protein suppresses autoimmune responses and establishes transplantation tolerance (13, 14). Assuming that CTLA-4 has multiple immune inhibitory roles, including trans-endocytosis of its ligands, further study of the cell-extrinsic and cell-intrinsic functions of this molecule will enable better control of physiological and pathological immune responses.