Begell House Inc.
Critical Reviews™ in Immunology
CRI
1040-8401
30
4
2010
Role of CD8 T-Cell-Mediated Autoimmune Diseases of the Central Nervous System
311-326
10.1615/CritRevImmunol.v30.i4.10
Martina
Deckert
Abteilung für Neuropathologie, Universitätsklinikum Köln, Köln, Germany
Monica
Sanchez-Ruiz
Abteilung für Neuropathologie, Universitätsklinikum Köln, Köln, Germany
Anna
Brunn
Abteilung für Neuropathologie, Universitätsklinikum Köln, Köln, Germany
Dirk
Schluter
Institut für Mikrobiologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Germany
CNS
autoimmunity
CD8 T cells
neuron
astrocyte
infection
Listeria monocytogenes
molecular mimicry
In T-cell-mediated autoimmune diseases of the central nervous system (CNS), CD4 T cells have long been regarded as the only pathogenetically relevant T-cell population. However, growing clinical and experimental evidence suggests that CD8 T cells also contribute significantly to autoimmune responses in the CNS. We discuss the potential induction of autoimmune CD8 T cells by infections, the impact of the microenvironment of the CNS on CD8 T-cell responses, and the potential interaction of CD8 T cells with autoantigen-expressing resident brain-cell populations—neurons in particular—in light of clinical and experimental findings.
Genetic Control of DH Reading Frame and Its Effect on B-Cell Development and Antigen-Specifc Antibody Production
327-344
10.1615/CritRevImmunol.v30.i4.20
Harry W.
Schroeder, Jr.
Division of Clinical Immunology and Rheumatology, Departments of Medicine, Microbiology, and Genetics, University of Alabama at Birmingham,USA
Michael
Zemlin
Department of Pediatrics, Philipps-University Marburg, Marburg, Germany
Mohamed
Khass
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
Huan H.
Nguyen
Principal Investigator, Viral Immunology Laboratory, International Vaccine Institute, Seoul, Korea
Robert L.
Schelonka
Division of Neonatology, Department of Pediatrics, University of Oregon Health Sciences Center, Portland, OR, USA
immunoglobulin
diversity gene segment
antibody repertoire
B-cell development
The power of the adaptive immune system to identify novel antigens depends on the ability of lymphocytes to create antigen receptors with diverse antigen-binding sites. For immunoglobulins, CDR (complementarity-determining region)-H3 lies at the center of the antigen-binding site, where it often plays a key role in antigen binding. It is created de novo by VDJ rearrangement and is thus the focus for rearrangement-dependent diversity. CDR-H3 is biased for the inclusion of tyrosine. In seeking to identify the mechanisms controlling CDR-H3 amino acid content, we observed that the coding sequence of DH gene segments demonstrate conservation of reading frame (RF)-specific sequence motifs, with RF1 enriched for tyrosine and depleted of hydrophobic and charged amino acids. Use of DH RF1 in functional VDJ transcripts is preferred from the earliest stages of B-cell development, "pushing" CDR-H3 to include specific categories of tyrosine-enriched antigen-binding sites. With development and maturation, the composition of the CDR-H3 repertoire appears to be “pulled” into a more refined specific range. Forcing the use of alternative DH RFs by means of gene targeting alters the expressed repertoire, enriching alternative sequence categories. This change in the repertoire variably affects antibody production and the development of specific B-cell subsets.
Tumor Antigen Presentation by Dendritic Cells
345-386
10.1615/CritRevImmunol.v30.i4.30
Troels R.
Petersen
Malaghan Institute of Medical Research, Wellington, New Zealand
Nina
Dickgreber
Malaghan Institute of Medical Research, Wellington, New Zealand
Ian F.
Hermans
Malaghan Institute of Medical Research, Wellington, New Zealand
dendritic cells
antigen presentation
tumor antigens
cross-presentation
NKT cells
Tumor cells are generally regarded as poor stimulators of naive T cells. In contrast, dendritic cells (DCs) are highly specialized in this function, and are therefore likely to be important intermediaries in the process of stimulating T cell responses to tumors. While providing solid evidence that DCs participate in antitumor immunity has proved difficult, several lines of evidence point in this direction. First, animal models involving bone marrow chimeras have shown that cells of hematopoeitic origin are required to elicit T cell responses to whole-tumor vaccines. Second, compared with other cells of hematopoeitic origin, DCs are particularly well-equipped to cross-present exogenous antigens to CD8+ T cells, a critical function if intermediary cells are involved. Third, tumor-infiltrating DCs purified from tumor samples have the capacity to cross-present tumor antigens in vitro. Finally, priming of anti-tumor T cell responses can be abrogated in new in vivo models in which DCs can be specifically depleted. It is therefore significant that DCs in cancer patients are often kept in an immature or dysfunctional state, thereby preventing stimulation of tumor-specific T cells. This review describes the different steps required for DCs to elicit T cell responses to tumor-associated antigens, and highlights processes that are amenable to intervention as therapy. We conclude that effective anti-tumor activity may be dependent on the ability to re-program DCs resident in the host, perhaps even when transferred autologous DCs generated ex vivo are used as vaccines. In this context, recruiting the activity of cells of the innate immune system to condition host DCs may help elicit more effective T cell-mediated responses.
The Role of Chemokines in Migration of Metastatic-like Lymphangioleiomyomatosis Cells
387-394
10.1615/CritRevImmunol.v30.i4.40
Gustavo
Pacheco-Rodriguez
Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
Joel
Moss
Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
cell motility
chemokines
chemokine receptors
cystic lung disease
lymphangioleiomyomatosis
metastasis
mammalian target of rapamycin
smooth muscle cells
tuberous sclerosis complex
Lymphangioleiomyomatosis (LAM), a rare cystic lung disease with multi-organ involvement, occurs primarily in women of childbearing age. LAM can present sporadically or in association with tuberous sclerosis complex (TSC). Loss of lung function in patients with LAM can be attributed to the dysregulated growth of LAM cells, with dysfunctional TSC1 or TSC2 genes, which encode hamartin and tuberin, respectively, leading to hyperactivation of the mammalian target of rapamycin (mTOR). LAM cells are smooth muscle-like cells that express melanoma antigens such as gp100, a splice variant of the Pmel17 gene. Tuberin and hamartin form heterodimers that act as negative regulators of mTOR. Lack of TSC2 function, as occurs in LAM cells, leads to the production of the chemokine CCL2/monocyte chemotactic protein 1 (MCP-1), which increases LAM cell mobility. Although many chemokines and their receptors could influence LAM cell mobilization, we propose that a positive-feedback loop is generated when dysfunctional TSC2 is present in LAM cells. We identified a group of chemokine receptors that is expressed in LAM cells and differs from those on smooth muscle and melanoma cells (Malme-3M). Chemokines have been implicated in tumor metastasis, and our data suggest a role for chemokines in LAM cell mobilization and thereby in the pathogenesis of LAM.