CD98 at the Crossroads of Adaptive Immunity and Cancer
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Commentary 1373 CD98 at the crossroads of adaptive immunity and cancer Joseph M. Cantor1 and Mark H. Ginsberg1,* Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA *Author for correspondence ([email protected]) Journal of Cell Science 125, 1373–1382 ß 2012. Published by The Company of Biologists Ltd doi: 10.1242/jcs.096040 Summary Adaptive immunity, a vertebrate specialization, adds memory and exquisite specificity to the basic innate immune responses present in invertebrates while conserving metabolic resources. In adaptive immunity, antigenic challenge requires extremely rapid proliferation of rare antigen-specific lymphocytes to produce large, clonally expanded effector populations that neutralize pathogens. Rapid proliferation and resulting clonal expansion are dependent on CD98, a protein whose well-conserved orthologs appear restricted to vertebrates. Thus, CD98 supports lymphocyte clonal expansion to enable protective adaptive immunity, an advantage that could account for the presence of CD98 in vertebrates. CD98 supports lymphocyte clonal expansion by amplifying integrin signals that enable proliferation and prevent apoptosis. These integrin-dependent signals can also provoke cancer development and invasion, anchorage-independence and the rapid proliferation of tumor cells. CD98 is highly expressed in many cancers and contributes to formation of tumors in experimental models. Strikingly, vertebrates, which possess highly conserved CD98 proteins, CD98-binding integrins and adaptive immunity, also display propensity towards invasive and metastatic tumors. In this Commentary, we review the roles of CD98 in lymphocyte biology and cancer. We suggest that the CD98 amplification of integrin signaling in adaptive immunity provides survival benefits to vertebrates, which, in turn, bear the price of increased susceptibility to cancer. Key words: CD98, Cell adhesion, Cell proliferation, Immunity, Integrin Introduction receptor components (V, D and J) through the action of The crucial role of clonal expansion in vertebrate recombination-activating gene (RAG) enzymes (Hsu, 2009). adaptive immunity This recombination mechanism generates tremendous diversity Journal of Cell Science All multicellular eukaryotic organisms initiate immune responses (Kuby, 1997) because there are many alleles for each V, D or J after recognizing common pathogen-associated molecular gene segment [or variable lymphocyte receptor (VLR)-A and patterns (PAMPs) on the surface of invading microbes VLR-B gene regions (Saha et al., 2010; Herrin and Cooper, 2010) (Medzhitov and Janeway, 1997). Pattern recognition receptors in the case of agnathans (jawless fish), discussed below], with (PRRs), including toll-like receptors (TLRs), nucleotide random nucleotide addition by terminal deoxynucleotidyl oligomerization domain (NOD)-like receptors (NLRs) and transferase (TdT) also adding junctional diversity. retinoic-acid-inducible gene I (RIG-I)-like receptors (RLRs; Possessing such a large repertoire of randomly generated RIG-I is also known as DDX58), generate signals that activate antigen specificities has obvious benefits (Murphy et al., 2011). ‘innate’ immune cells (Kumar et al., 2011) to neutralize or First, the greater diversity of antigen receptors enables the destroy viruses and bacteria either through reactive chemicals neutralization of a correspondingly larger diversity of pathogens [reactive oxygen species (ROS), reactive nitrogen species (RNS) and makes evasion of their neutralizing effects more challenging etc.], complement or enzymatic digestion (lysozyme, etc.) (Tosi, for pathogens. Second, greater diversity combined with efficient 2005; Leclerc and Reichhart, 2004). This process must be deletion of self-reactive cells (Fig. 1) enables more specific repeated every time the organism is exposed to the same targeting of pathogens rather than host tissues. Third, increased pathogen. However, many pathogens that infect higher organisms specificity combined with expansion of pathogen-specific can overcome innate immunity and thus maintain infections that lymphocytes allows for formation of specific recall or result in serious damage to the host. ‘memory’ responses (Sprent and Surh, 2002). Maintaining a Vertebrates utilize an additional powerful weapon against few memory cells that rapidly expand in response to previously pathogens, namely, adaptive immunity. Adaptive immune experienced antigen conserves resources that would otherwise be responses provide long-lasting, flexible and specific protection expended in maintaining a large population of cells that to a wider variety of pathogens than innate immunity alone encompass the entire repertoire of recognition specificities (Boehm, 2011). Lymphocytes or lymphocyte-like cells are the (Murphy et al., 2011). The stimulation of this memory central adaptive immune cell. They each express unique antigen mechanism by vaccines underlies the protection that has saved receptors of a single specificity on their surface. As they develop millions of lives. For these reasons, the vertebrate immune from lymphoid progenitor cells in the bone marrow, lymphocytes system is usually viewed as more complex and potent than that of randomly rearrange gene segments that encode three antigen invertebrates with respect to diversity, specificity and memory 1374 Journal of Cell Science 125 (6) (Boehm, 2011). These benefits depend on the rapid proliferation hypermutation of receptor genes to increase affinity for antigen, of lymphocytes that results in clonal expansion, which thus and thus can last up to 3 weeks (Murphy et al., 2011). Both B and T functions as a keystone of adaptive immunity (Fig. 1), allowing cell clonal expansion rely on the capacity of lymphocytes to vertebrates to take advantage of the striking specificity and accelerate from a resting state to sustained rapid proliferation. diversity of adaptive immunity, while conserving metabolic Several molecules and mechanisms assist in this process, including resources. growth cytokines or receptors (Nelson and Willerford, 1998; Clonal expansion requires resting lymphocytes to enter the cell Weaver et al., 2007), adhesion molecules (Mitchell and Williams, cycle rapidly upon receiving the appropriate activation signals 2010), anti-apoptotic proteins (Hildeman et al., 2007) and the from antigen receptors, co-receptors, co-stimulatory molecules and vertebrate-specific transmembrane protein CD98 (Cantor et al., cytokines. Extremely rapid cellular proliferation must then follow 2009; Cantor et al., 2011). (with doubling times of less than 5 hours) in order to differentiate and generate sufficient effector cells in time (typically in less 5 CD98: more than a lymphocyte activation marker days) (Abbas, 2003). For B cells, this rapid proliferation phase The CD98 heterodimer consists of a type II single-pass can also occur several times, with accompanying somatic transmembrane heavy chain (CD98hc, also known as 4F2 Spleen, lymph nodes Plasma Self-reactive B cells cells are destroyed IgG Memory B cell IgA B cell antigen receptors Diverse resting B cells light chain VJ rearrangement Pathogens IgM heavy chain VDJ rearrangement Free virus Extracellular bacteria Parasites Bone marrow Clonal expansion Virus-infected cells Tumor cells Lymphoid progenitor cell Intracellular bacteria Cytokine ‘help’ for B cells Journal of Cell Science Antigen-presenting cell T cell antigen receptors (APC) Memory CD4+ T cell alpha chain VJ rearrangement CD4+ beta chain VDJ rearrangement ‘Helper’ T cells Diverse resting T cellss CytokineCytokoki ‘help’ for CTL Self-reactive T cells are destroyed CD8+ Cytotoxic (CTL) Thymus ‘‘k‘killer’ T cellss Memory CD8+ T cell Infected host cell Fig. 1. Vertebrate adaptive immunity. Antigen diversity in jawed vertebrates is generated by somatic recombination of the V, D and J regions (variable, diversity and joining immunoglobulin gene regions) in both immunoglobulin (Ig, B-cell receptor) and TCR (T-cell receptor) chains. After their development in bone marrow (and thymus for T cells), the clones that express self-reactive antigen receptors are deleted. Very few mature resting B and T cells are maintained for each specific antigen (indicated with different colors), thus conserving valuable metabolic resources. Upon antigen exposure in the periphery, the appropriate lymphocyte clone(s) are expanded quickly through rapid proliferation to generate large numbers of antigen-specific effector cells (clonal expansion, illustrated by the green triangles). Effector B cells secrete soluble receptors (antibodies, i.e. IgG, IgA and IgM) that can neutralize or eliminate extracellular pathogens. Cytotoxic (CD8+) T cells scan host cells for the presence of virus or intracellular bacteria, killing any cells that are infected. Helper (CD4+) T cells secrete cytokines that boost both cytotoxic T cells and effector B cells for efficient class-switched antibody responses. Most effector cells die after pathogen clearance, leaving only small numbers of memory B and T cells that are poised for a more rapid clonal expansion upon a secondary exposure (illustrated by the pink triangles). Thus, adaptive immunity utilizes clonal expansion to provide long-lasting specific protection against a wide variety of pathogens while minimizing nutrient cost to the host. IgG, immunoglobulin c; IgA, immunoglobulin a; IgM, immunoglobulin m. CD98, cancer and immunity 1375 antigen heavy chain or FRP-1; encoded by the genes SLC3A2 and 2001; Mori et al., 2004; Ohgimoto et al., 1996;