- Email: [email protected]
Antigen processing and recognition
11
Antigen processing and recognition Editorial overview Peter Cresswell* and Antonio Lanzavecchia† Addresses *Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, PO Box 208011, New Haven, CT 06520-8011, USA; e-mail: [email protected] † Institute of Research for Biomedicine, Via Vela 6, CH 6500, Bellinzona, Switzerland; e-mail: [email protected] Current Opinion in Immunology 2001, 13:11–12 0952-7915/01/$ — see front matter © 2001 Elsevier Science Ltd. All rights reserved.
Generation of MHC-class-I−peptide complexes begins with the source of the peptides, in the cytosol. Yewdell and Bennink (pp 13−18) provide an overview of recent advances in our understanding of the mechanisms by which these peptides are produced. For a number of years it has been known that the proteasome is the major protease responsible for cleaving cytosolic proteins and thus generating these peptides. It now appears that the majority of the peptides derived from proteasomal degradation and which ultimately associate with class I molecules come from proteins that have recently been synthesized. A large fraction of newly synthesized proteins in yeast have recently been shown to be degraded — because of aberrant folding, premature termination or other reasons [1] — and a similar phenomenon in mammalian cells could account for the dominance of peptides derived from the newly synthesized pool of proteins destined for class I molecules. The roles in antigen-processing of the IFN-γ-inducible proteasome β-subunits, which are incorporated into the socalled immunoproteasome, as well as the IFN-γ-inducible components that make up the 11S or PA28 modifier of the 20S proteasome have also seen significant attention. Perhaps the most surprising finding here is the observation that the absence of the 11S α-subunit not only produces clear defects in antigen processing in the mouse lacking it but also affects the incorporation of LMP2, LMP7 and MECL1 — the immunoproteasome-specific β-subunits — into the proteasome [2]. The above findings, combined with data clearly showing trimming of peptides prior to their association with class I molecules, constitute significant progress in the understanding of peptide generation. This stands in contrast to the limited progress made in understanding the subsequent events in peptide association with class I molecules. The past year has seen the generation of tapasin-deficient mice [3,4]. These have the anticipated defects in the formation of class-I−peptide complexes but their existence has done little to explain how tapasin works. We are also left to puzzle over the roles of the other components of the class-I-loading complex: TAP, calreticulin and ERp57. The peptide translocation role of TAP is the only well-established function of an
individual component of the complex. The roles of the other components remain to be established. Matsuda and Kronenberg (pp 19−25) review recent progress in the CD1 field. CD1d molecules are expressed in both humans and rodents, but CD1a, b and c subtypes are absent from mice and rats. The structures of a number of lipids bound by CD1b, c and d molecules have been determined. Some are mycobacterial and antigenic, and are recognized by T cells in association with CD1b or c; some are self-lipids recognized in association with CD1b or d by autoreactive T cells. The recognition of CD1dassociated α-galactosyl ceramide, a lipid isolated from marine sponges, by the majority of NKT cells in both humans and mice remains essentially unexplained biologically. However, tetramers of CD1d associated with this lipid can now be used to track NKT cells. Interesting advances have been made in delineating the differences in intracellular trafficking of the CD1 subtypes which are based on differences in the endocytic motifs in their cytoplasmic domains. CD1a lacks such an endocytic motif and is restricted to the plasma membrane and early endosomes. The other CD1 molecules penetrate deeper into the endocytic pathway and thus gain access to a different set of lipids. This may be important in ensuring that a variety of lipids can be sampled by the CD1 system because lipids with different acyl chain lengths and/or degrees of saturation sort into different endocytic compartments. The biochemical mechanisms responsible for shifting lipids from the comfort of the membrane bilayer to the CD1 binding groove remain a mystery. Different aspects of the MHC class II antigen processing field are reviewed by Watts (pp 26−31), and by Siemasko and Clark (pp 32−36). The latter review the important role of signalling by the BCR-associated Igα and Igβ molecules in antigen processing and presentation by B cells. Watts focuses on the mechanisms in the endocytic pathway that facilitate the production of peptides associated with class II molecules. Mice lacking many lysosomal proteases are now available and the respective roles of the proteases in antigen processing have been evaluated. Some, such as cathepsins B and D, may not be essential; others are more important, particularly cathepsin S which plays an important role in invariant-chain degradation. However, different antigens in association with different MHC class II alleles may have different protease requirements and absolute assignation of individual cathepsins to the categories of ‘necessary’ or ‘unnecessary’ may be premature. An IFN-γ-inducible lysosomal thiol reductase (GILT), which is constitutively expressed in antigen-presenting cells, has been identified [5]. This enzyme may play a role
12
Antigen processing and recognition
in the reduction of proteins in the endocytic pathway which is required for the generation of certain class-IIrestricted antigenic peptides. A puzzle still unresolved is the precise mechanism by which the DM molecule induces peptide exchange by MHC class II α−β dimers. Mutagenesis of the HLA-DR molecule has further delineated the surface that interacts with DM [6]; we still await the determination of the complementary surface of DM. Pieters (pp 37−44) reviews the mechanisms of bacterial evasion from host defence. Some bacteria exploit the target-cell machinery to enter and survive in nonphagocytic cells. Others are taken up by phagocytes but either escape from the phagosome into the cytosol or prevent phagolysosomal fusion, thereby avoiding being digested. A striking example is provided by Mycobacterium tuberculosis, which enters the macrophage via cholesterol-enriched membrane microdomains that are coated on the cytoplasmic side with TACO, a protein that prevents fusion with lysosomes [7]. The identification of bacterial genes that control bacterial evasion capacity in mammalian cells is now a close goal thanks to the sequencing of bacterial genomes and will certainly impact on our capacity to design more effective vaccines. A particularly active area of research has focused on dendritic cells, the professional antigen-presenting cells that initiate the T cell response (see the review by Théry and Amigorena [pp 45−51]). In their immature state, dendritic cells are characterised by high and broad antigen-capturing capacity. Novel surface receptors have been discovered on dendritic cells. Two C-type lectins, Langerin and DC-SIGN, are involved in formation of Birbeck granules in Langerhans cells and in binding and transfer of HIV by migrating dendritic cells. Furthermore, it has been shown that CD91 can act as a receptor for gp96, allowing its internalization, which is followed by presentation of gp96-bound peptides on MHC class I molecules. Several studies have shown that in both human and mouse dendritic cells, the maturation process induced by pathogens shuts off macropinocytosis, while
boosting antigen processing, MHC synthesis and loading, and formation of stable peptide−MHC complexes. The differences observed in the underlying mechanisms may be related to the species difference or to the type of culture system used to generate dendritic cells. Maturing MHC class I and class II molecules are segregated into secretory vesicles that are inserted in the plasma membrane, thereby optimizing the formation of the immunological synapse [8]. It has been shown that dendritic cells have the unique capacity to present exogenous antigens on MHC class I molecules and a recent study from Amigorena’s group demonstrates that in dendritic cells, but not in macrophages, low molecular weight molecules are selectively transported from the endosomes to the cytosol, gaining access to the classical pathway of class-I-restricted antigen presentation [9].
References 1.
Turner GC, Varshavsky A: Detecting and measuring cotranslational protein degradation in vivo. Science 2000, 289:2117-2120.
2.
Preckel T, Fung-Leung WP, Cai Z, Vitiello A, Salter-Cid L, Winqvist O, Wolfe TG, Von Herrath M, Angulo A, Ghazal P et al.: Impaired immunoproteasome assembly and immune responses in PA28-//mice. Science 1999, 286:2162-2165.
3.
Grandea AG III, Golovina TN, Hamilton SE, Sriram V, Spies T, Brutkiewicz RR, Harty JT, Eisenlohr LC, Van Kaer L: Impaired assembly yet normal trafficking of MHC class I molecules in tapasin mutant mice. Immunity 2000, 13:213-222.
4.
Garbi N, Tan P, Diehl AD, Chamber BJ, Ljunggren H-G, Momburg F, Hammerling GJ: Impaired immune responses and altered peptide repertoire in tapasin-deficient mice. Nat Immunol 2000, 1:234-238.
5.
Phan UT, Arunachalam B, Cresswell P: Gamma-interferon-inducible lysosomal thiol reductase (GILT). Maturation, activity, and mechanism of action. J Biol Chem 2000, 275:25907-25914.
6.
Doebele RC, Busch R, Scott HM, Pashine A, Mellins ED: Determination of the HLA-DM interaction site on HLA-DR molecules. Immunity 2000, 13:517-527.
7.
Gatfield J, Pieters J: Essential role for cholesterol in entry of mycobacteria in macrophages. Science 2000, 288:1647-1650.
8.
Turley SJ, Inaba K, Garrett WS, Ebersold M, Unternaheher J, Steinman RM, Mellman I: Transport of peptide-MHC class II complexes in developing dendritic cells. Science 2000, 288:522-527.
9.
Rodriguez A, Regnault A, Kleijmeer M, Ricciardi-Castagnoli P, Amigorena S: Selective transport of internalized antigen to the cytosol for MHC class I presentation in dendritic cells. Nat Cell Biol 1999, 1:362-368.
Antigen processing and recognition Editorial overview Peter Cresswell* and Antonio Lanzavecchia† Addresses *Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 310 Cedar Street, PO Box 208011, New Haven, CT 06520-8011, USA; e-mail: [email protected] † Institute of Research for Biomedicine, Via Vela 6, CH 6500, Bellinzona, Switzerland; e-mail: [email protected] Current Opinion in Immunology 2001, 13:11–12 0952-7915/01/$ — see front matter © 2001 Elsevier Science Ltd. All rights reserved.
Generation of MHC-class-I−peptide complexes begins with the source of the peptides, in the cytosol. Yewdell and Bennink (pp 13−18) provide an overview of recent advances in our understanding of the mechanisms by which these peptides are produced. For a number of years it has been known that the proteasome is the major protease responsible for cleaving cytosolic proteins and thus generating these peptides. It now appears that the majority of the peptides derived from proteasomal degradation and which ultimately associate with class I molecules come from proteins that have recently been synthesized. A large fraction of newly synthesized proteins in yeast have recently been shown to be degraded — because of aberrant folding, premature termination or other reasons [1] — and a similar phenomenon in mammalian cells could account for the dominance of peptides derived from the newly synthesized pool of proteins destined for class I molecules. The roles in antigen-processing of the IFN-γ-inducible proteasome β-subunits, which are incorporated into the socalled immunoproteasome, as well as the IFN-γ-inducible components that make up the 11S or PA28 modifier of the 20S proteasome have also seen significant attention. Perhaps the most surprising finding here is the observation that the absence of the 11S α-subunit not only produces clear defects in antigen processing in the mouse lacking it but also affects the incorporation of LMP2, LMP7 and MECL1 — the immunoproteasome-specific β-subunits — into the proteasome [2]. The above findings, combined with data clearly showing trimming of peptides prior to their association with class I molecules, constitute significant progress in the understanding of peptide generation. This stands in contrast to the limited progress made in understanding the subsequent events in peptide association with class I molecules. The past year has seen the generation of tapasin-deficient mice [3,4]. These have the anticipated defects in the formation of class-I−peptide complexes but their existence has done little to explain how tapasin works. We are also left to puzzle over the roles of the other components of the class-I-loading complex: TAP, calreticulin and ERp57. The peptide translocation role of TAP is the only well-established function of an
individual component of the complex. The roles of the other components remain to be established. Matsuda and Kronenberg (pp 19−25) review recent progress in the CD1 field. CD1d molecules are expressed in both humans and rodents, but CD1a, b and c subtypes are absent from mice and rats. The structures of a number of lipids bound by CD1b, c and d molecules have been determined. Some are mycobacterial and antigenic, and are recognized by T cells in association with CD1b or c; some are self-lipids recognized in association with CD1b or d by autoreactive T cells. The recognition of CD1dassociated α-galactosyl ceramide, a lipid isolated from marine sponges, by the majority of NKT cells in both humans and mice remains essentially unexplained biologically. However, tetramers of CD1d associated with this lipid can now be used to track NKT cells. Interesting advances have been made in delineating the differences in intracellular trafficking of the CD1 subtypes which are based on differences in the endocytic motifs in their cytoplasmic domains. CD1a lacks such an endocytic motif and is restricted to the plasma membrane and early endosomes. The other CD1 molecules penetrate deeper into the endocytic pathway and thus gain access to a different set of lipids. This may be important in ensuring that a variety of lipids can be sampled by the CD1 system because lipids with different acyl chain lengths and/or degrees of saturation sort into different endocytic compartments. The biochemical mechanisms responsible for shifting lipids from the comfort of the membrane bilayer to the CD1 binding groove remain a mystery. Different aspects of the MHC class II antigen processing field are reviewed by Watts (pp 26−31), and by Siemasko and Clark (pp 32−36). The latter review the important role of signalling by the BCR-associated Igα and Igβ molecules in antigen processing and presentation by B cells. Watts focuses on the mechanisms in the endocytic pathway that facilitate the production of peptides associated with class II molecules. Mice lacking many lysosomal proteases are now available and the respective roles of the proteases in antigen processing have been evaluated. Some, such as cathepsins B and D, may not be essential; others are more important, particularly cathepsin S which plays an important role in invariant-chain degradation. However, different antigens in association with different MHC class II alleles may have different protease requirements and absolute assignation of individual cathepsins to the categories of ‘necessary’ or ‘unnecessary’ may be premature. An IFN-γ-inducible lysosomal thiol reductase (GILT), which is constitutively expressed in antigen-presenting cells, has been identified [5]. This enzyme may play a role
12
Antigen processing and recognition
in the reduction of proteins in the endocytic pathway which is required for the generation of certain class-IIrestricted antigenic peptides. A puzzle still unresolved is the precise mechanism by which the DM molecule induces peptide exchange by MHC class II α−β dimers. Mutagenesis of the HLA-DR molecule has further delineated the surface that interacts with DM [6]; we still await the determination of the complementary surface of DM. Pieters (pp 37−44) reviews the mechanisms of bacterial evasion from host defence. Some bacteria exploit the target-cell machinery to enter and survive in nonphagocytic cells. Others are taken up by phagocytes but either escape from the phagosome into the cytosol or prevent phagolysosomal fusion, thereby avoiding being digested. A striking example is provided by Mycobacterium tuberculosis, which enters the macrophage via cholesterol-enriched membrane microdomains that are coated on the cytoplasmic side with TACO, a protein that prevents fusion with lysosomes [7]. The identification of bacterial genes that control bacterial evasion capacity in mammalian cells is now a close goal thanks to the sequencing of bacterial genomes and will certainly impact on our capacity to design more effective vaccines. A particularly active area of research has focused on dendritic cells, the professional antigen-presenting cells that initiate the T cell response (see the review by Théry and Amigorena [pp 45−51]). In their immature state, dendritic cells are characterised by high and broad antigen-capturing capacity. Novel surface receptors have been discovered on dendritic cells. Two C-type lectins, Langerin and DC-SIGN, are involved in formation of Birbeck granules in Langerhans cells and in binding and transfer of HIV by migrating dendritic cells. Furthermore, it has been shown that CD91 can act as a receptor for gp96, allowing its internalization, which is followed by presentation of gp96-bound peptides on MHC class I molecules. Several studies have shown that in both human and mouse dendritic cells, the maturation process induced by pathogens shuts off macropinocytosis, while
boosting antigen processing, MHC synthesis and loading, and formation of stable peptide−MHC complexes. The differences observed in the underlying mechanisms may be related to the species difference or to the type of culture system used to generate dendritic cells. Maturing MHC class I and class II molecules are segregated into secretory vesicles that are inserted in the plasma membrane, thereby optimizing the formation of the immunological synapse [8]. It has been shown that dendritic cells have the unique capacity to present exogenous antigens on MHC class I molecules and a recent study from Amigorena’s group demonstrates that in dendritic cells, but not in macrophages, low molecular weight molecules are selectively transported from the endosomes to the cytosol, gaining access to the classical pathway of class-I-restricted antigen presentation [9].
References 1.
Turner GC, Varshavsky A: Detecting and measuring cotranslational protein degradation in vivo. Science 2000, 289:2117-2120.
2.
Preckel T, Fung-Leung WP, Cai Z, Vitiello A, Salter-Cid L, Winqvist O, Wolfe TG, Von Herrath M, Angulo A, Ghazal P et al.: Impaired immunoproteasome assembly and immune responses in PA28-//mice. Science 1999, 286:2162-2165.
3.
Grandea AG III, Golovina TN, Hamilton SE, Sriram V, Spies T, Brutkiewicz RR, Harty JT, Eisenlohr LC, Van Kaer L: Impaired assembly yet normal trafficking of MHC class I molecules in tapasin mutant mice. Immunity 2000, 13:213-222.
4.
Garbi N, Tan P, Diehl AD, Chamber BJ, Ljunggren H-G, Momburg F, Hammerling GJ: Impaired immune responses and altered peptide repertoire in tapasin-deficient mice. Nat Immunol 2000, 1:234-238.
5.
Phan UT, Arunachalam B, Cresswell P: Gamma-interferon-inducible lysosomal thiol reductase (GILT). Maturation, activity, and mechanism of action. J Biol Chem 2000, 275:25907-25914.
6.
Doebele RC, Busch R, Scott HM, Pashine A, Mellins ED: Determination of the HLA-DM interaction site on HLA-DR molecules. Immunity 2000, 13:517-527.
7.
Gatfield J, Pieters J: Essential role for cholesterol in entry of mycobacteria in macrophages. Science 2000, 288:1647-1650.
8.
Turley SJ, Inaba K, Garrett WS, Ebersold M, Unternaheher J, Steinman RM, Mellman I: Transport of peptide-MHC class II complexes in developing dendritic cells. Science 2000, 288:522-527.
9.
Rodriguez A, Regnault A, Kleijmeer M, Ricciardi-Castagnoli P, Amigorena S: Selective transport of internalized antigen to the cytosol for MHC class I presentation in dendritic cells. Nat Cell Biol 1999, 1:362-368.