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1184 Part IX: Lymphocytes and Plasma Cells Chapter 76: Functions of T Lymphocytes: T-cell Receptors for Antigen 1185

CTLA-4 (CD152) In general, the molecular mechanisms of T-cell costimulation and
CTLA-4 (CD152) is another receptor for CD80 and CD86. It is a 50-kDa coinhibition are viewed as an evolving concept, as receptors and lig-
disulfide-linked homodimer that shares 31 percent identity with CD28. ands exhibit great diversity in their expression, structure and function,
The gene encoding this receptor is closely linked with that encoding and this is likely to be dependent on the context of anatomical loca-
CD28 on the long arm of chromosome 2 at 2q33–q34. However, in con- tion and the existence of underlying healthy and pathological immune
trast to the constitutive expression of CD28, T cells—with the exception responses. 120
of T REGs —express CD152 only upon activation. Expression of CD152
peaks at approximately 24 hours after activation and then subsides by
72 hours but is always approximately 30- to 50-fold lower than that of T-CELL ADHESION MOLECULES
CD28. CD28 ligation is particularly effective in inducing CD152. In addition to CD3/TCR molecules and CD4 or CD8, several other
CD152 binds to both CD80 and CD86 using the same highly con- surface proteins are required for efficient T-cell antigen recognition.
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served motif (MYPPPY) used by CD28, which, like CD28, is also in Some of these surface proteins are termed adhesion molecules, as they
a loop that resembles the third complementarity-determining region facilitate the adhesion of the T cell to its appropriate APC or target cell
of immunoglobulin molecules. However, despite its lower expression (Fig. 76–4). Their main function is to permit the T-cell antigen receptor
levels, CD152 binds to CD80 and CD86 approximately 20 times more complex to interact better with the MHC glycoproteins of the other cell,
avidly than CD28, with a Kd of 0.4 and 2.2 μM, respectively. 107,108 In allowing for efficient T-cell antigen recognition and activation. Each
contrast to CD28, ligation of CD152 transmits a negative signal to member of this group of accessory molecules has distinctive affinities
T-cell activation. Instead of an ITAM, CD152 possesses an immuno- for the surface molecules expressed by the APC or target cell, which is
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receptor tyrosine inhibitory motif (ITIM) in its cytoplasmic domain. reflected by differential expression patterns on specific T-cell subsets.
Ligation of CD152 induces tyrosine phosphorylation of the ITIM, Adhesion and antigen response are largely considered the final step of
which, in turn, recruits the tyrosine phosphatase SHP-2 that can deac- the multi-stage T-cell trafficking process that involves migration, adhe-
tivate the phosphorylated ITAMs of the ζ chains of the TCR complex. sion, and signaling.
Mice made genetically deficient in CD152 develop a fatal lymphopro-
liferative disorder that is characterized by massive cell activation and
infiltration into tissues, indicating that CD152 serves as an important Lymphocyte Function-Associated Glycoproteins
brake on unregulated T-cell activation. Mice that are genetically The lymphocyte function-associated (LFA) molecules are an impor-
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modified to express only the extracellular domain of CD152 allow- tant family of glycoproteins that facilitate efficient cell–cell adhesion.
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ing the binding of CD80 or CD86, however, are protected from organ The family consists of the three major surface molecules LFA-1, LFA-2
infiltration by T cells, suggesting that modulation of CD28 signals by (CD2), and LFA-3 (CD58). LFA-1 belongs to a family of three related
competitive sequestration of its ligands can regulate tissue infiltration glycoproteins LFA-1, MAC-1 (CD11b/CD18), and gp150,95 (CD11c/
by autoreactive T cells. 116 CD18). These proteins also are called “integrins” because they are
Moreover, anti-CD152 monoclonal antibodies that block the inter- hypothesized to coordinate the binding of cells to other cell types and
action of CD152 with CD80 and CD86 can enhance T-cell responses to extracellular proteins. Each protein consists of a distinct α subunit
in vitro and in vivo. This has prompted their evaluation as immune- noncovalently associated with the β subunit glycoprotein of 95 kDa,
2
enhancing agents in models of autoimmune disease and in transplan- designated as CD18. Because they share a common β subunit, these
2
tation models, and more recently in clinical vaccine studies and molecules also are referred to as the β integrins. The α subunit of LFA-
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2
trials in combination with the blockade of other immunomodulatory 1, designated CD11a, is a 180-kDa glycoprotein. Coupled together with
molecules. 118,119 the common β subunit, this 180-kDa molecule is expressed on more
2
than one-third of all marrow cells, all T cells, all B cells, and all NK
Other Members of the CD28 Receptor Family cells. The α subunit of MAC-1 is a glycoprotein of 170 kDa, designated
Homology-based cloning strategies have identified other proteins that CD11b. MAC-1 is expressed on NK cells, monocytes, macrophages,
are structurally related to CD28/CTLA-4 or its ligands CD80/CD86. granulocytes, and small subpopulations of T and B cells. The α subunit
These proteins are categorized as members of the CD28 or CD80 (B7) of p150,95, designated CD11c, is a 150-kDa glycoprotein that is not
families, respectively, which belong to the immunoglobulin superfam- expressed by T lymphocytes.
ily, a structurally and functionally highly heterogeneous family of T-cell The shared β subunit (CD18) has extensive sequence homology
2
cosignaling molecules. 120 to the β subunit (CD61) of the platelet adhesion receptor glycopro-
3
Two other important members of the CD28 family are iCOS tein IIb/IIIa (CD41/CD61) and the β subunit (CD29) of a family of
1
(CD278) and PDCD1 (CD279, PD-1). Whereas CD278 is found pri- related adhesion proteins, termed very-late-activation (VLA) anti-
marily on activated T cells, CD279 can be found on activated T cells, gens. Many of these receptors function in cell–cell interactions and
B cells, some myeloid cells, and NK cells. CD278 and CD279, respec- recognize their ligands at sites that contain the amino acid sequence
tively, bind to the iCOS-ligand (iCOS-L or CD275) and the PD-ligands Arg-Gly-Asp. In addition, the α subunit provides some selectivity.
PD-L1 (CD274) or PD-L2 (CD273). CD273, CD274, and CD275 LFA-1, because of its α subunit, binds best to cell-surface ligands called
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belong to the CD80 (B7) family of surface molecules and are found ICAMs, namely, ICAM-1 (CD54), ICAM-2 (CD102), and ICAM-3
or can be induced on B cells, APCs, and other nonhematopoietic tis- (CD50). CD54 and CD102 are expressed on endothelial cells as well
sues. CD278 primarily functions as a costimulatory molecule for cells as APCs. The binding of LFA-1 on lymphocytes to these molecules
bearing CD275. CD279 plays a negative regulatory role on activated allows lymphocytes to migrate through blood vessel walls. CD50 is
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T cells and modifies T cell/APC contact durations by inhibiting TCR expressed only on leukocytes, including T cells, and is thought to play
stop signals. Like CD152, CD279 possesses an ITIM motif in its cyto- an important role in the adhesion of T cells with LFA-1 expressed on
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plasmic tail that, upon phosphorylation, can recruit the tyrosine phos- APCs (see Fig. 76–4). The LFA glycoproteins are essential for proper
phatase SHP-2. In this regard, CD279 may play a role similar to that T-cell function and host immunity, and integrin gene defects leading
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of CD152, helping to brake cellular activation when bound to its ligands to leukocyte adhesion deficiencies result in severe immune deficien-
CD273 or CD274. cies. In humans, three LADs (LAD I to III) have been described.
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