Biomedical subjects

Claudia Kemper

Publications and source records attributed to Claudia Kemper.

8 recordsLinked to original sources

PubMed2005

Emerging roles and new functions of CD46.

In the past 20 years, our understanding of the workings of complement regulatory protein, CD46 (membrane cofactor protein), has grown as has the impressive list of pathogens interacting with this membrane-bound complement inhibitor. Referred to as a "pathogen magnet," CD46 serves as a receptor for seven human pathogens. Initially discovered as a widely expressed C3b- and C4b-binding protein, it was subsequently shown to be a cofactor for the serine protease factor I to inactivate by limited proteolysis these two opsonins and components of the convertases. The involvement of CD46 in reproductive processes continues to be an emerging story. It is a protector of placental tissue, but it may also play a more direct role in reproduction through its expression on the inner acrosomal membrane of spermatozoa. Cross-linking CD46 with antibodies or natural or pathogenic ligands induces rapid turnover and signaling events. In this regard, much attention is currently focused on generating human T lymphocyte regulatory cells by cross-linking CD46. Finally, highlighting its importance in protecting cells against excessive complement activation is the discovery that even a heterozygous deficiency of CD46 predisposes to hemolytic uremic syndrome.

Amino Acid Sequence↗

PubMed2005

Complement-induced regulatory T cells suppress T-cell responses but allow for dendritic-cell maturation.

Concurrent activation of the T-cell receptor (TCR) and complement regulator CD46 on human CD4+ T lymphocytes induces Tr1-like regulatory T cells that suppress through IL-10 secretion bystander T-cell proliferation. Here we show that, despite their IL-10 production, CD46-induced T-regulatory T cells (Tregs) do not suppress the activation/maturation of dendritic cells (DCs). DC maturation by complement/CD46-induced Tregs is mediated through simultaneous secretion of GM-CSF and soluble CD40L, factors favoring DC differentiation and reversing inhibitory effects of IL-10. Thus, CD46-induced Tregs produce a distinct cytokine profile that inhibits T-cell responses but leaves DC activation unimpaired. Such "DC-sparing" Tregs could be desirable at host/environment interfaces such as the gastrointestinal tract where their specific cytokine profile provides a mechanism that ensures unresponsiveness to commensal bacteria while maintaining reactivity to invading pathogens.

Antigens, CD↗

PubMed2005

Induction of a regulatory phenotype in human CD4+ T cells by streptococcal M protein.

Regulatory T cells (Tregs) participate in the control of the immune response. In the human system, an IL-10-secreting, T regulatory type 1 cell (Tr1)-like subset of Tregs can be induced by concurrent cross-linking of the TCR and CD46 on naive CD4(+) T cells. Because many viral and bacterial pathogens, including the major human pathogen Streptococcus pyogenes, bind to CD46, we asked whether this bacterium can directly induce Tr1-like cells through the streptococcal ligand for CD46, the M protein. The M5 and M22 proteins were found to induce T cells to develop into the IL-10-producing Tr1-like phenotype. Moreover, whole M5-expressing bacteria, but not isogenic M-negative bacteria, led to proliferation and IL-10 secretion by T cells. The interaction between the M5 protein and T cells was dependent on CD46 and the conserved C repeat region of M5. Supernatants derived from T cells stimulated with M proteins or M protein-expressing bacteria suppressed bystander T cell proliferation through IL-10 secretion. In addition, activation of CD46 through streptococcal M protein induced the expression of granzyme B, providing a second means for these cells to regulate an immune response. These findings suggest that binding to CD46 and exploiting its signaling pathway may represent a strategy employed by a number of important human pathogens to induce directly an immunosuppressive/regulatory phenotype in T cells.

Antigens, Bacterial↗

PubMed2005

T-cell stimulation and regulation: with complements from CD46.

Crosslinking of CD46 and CD3 on naïve human CD4+ T-lymphocytes induces interleukin-10 secretion and granzyme B expression. These highly proliferative T-regulatory type 1-like T-regulatory T-cells (Tregs) can suppress an immune response. We propose that this process is important in the prevention of chronic inflammation such as at epithelial borders and in deactivation of a successful immune response. Relative to the latter, once a complement-fixing polyclonal antibody response has been mounted, in most cases, the pathogen will be rapidly destroyed. At this time, the C3b/C4b-bearing immune complexes could initiate the deactivation arm of an immune response by shutting down immunocompetent cells through CD46-generated T-cells. Herein, we review this pathway for the induction of Tregs, focusing on a role for the complement system and especially signaling through CD46 on human T-cells.

Amino Acid Sequence↗

PubMed2004

Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells.

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells use the perforin/granzyme pathway as a major mechanism to kill pathogen-containing cells and tumor cells.(1,2) Dysregulation of this pathway results in several human diseases, such as hemophagocytic lymphohistiocytosis. Here we characterize the single-cell expression pattern of granzymes A and B in human lymphocytes using a flow cytometry-based assay. We demonstrate that most circulating CD56(+)8(-) NK cells, and approximately half of circulating CD8(+) T lymphocytes, coexpressed both granzymes A and B. In contrast, few circulating CD4(+) T lymphocytes expressed granzymes A or B. Activation of CD8(+) T lymphocytes with concanavalin A (ConA)/interleukin-2 (IL-2), and activation of CD4(+) T lymphocytes with antibodies to CD3/CD28 or CD3/CD46 (to generate T regulatory [Tr1] cells), induced substantial expression of granzyme B, but not granzyme A. Naive CD4(+)CD45RA(+) cells stimulated with antibodies to CD3/CD46 strongly expressed granzyme B, while CD3/CD28 stimulation was ineffective. Finally, we show that granzyme B-expressing CD4(+) Tr1 cells are capable of killing target cells in a perforin-dependent, but major histocompatibility complex (MHC)/T-cell receptor (TCR)-independent, manner. Our results demonstrate discordant expression of granzymes A and B in human lymphocyte subsets and T regulatory cells, which suggests that different granzymes may play unique roles in immune system responses and regulation.

Animals↗

PubMed2004

CD46: expanding beyond complement regulation.

During the 1980s CD46 was discovered in a search for C3b binding proteins of human peripheral blood cells. Its role as an inactivator of C3b and C4b deposited on self-tissue is highlighted by the observation that partial deficiency of CD46 is a predisposing factor to hemolytic uremic syndrome. This discovery has an impact on the treatment options for these patients. Other new findings have expanded the role of CD46 in immunity and disease. For example, signaling through CD46 on human T lymphocytes drives them to become regulatory cells, indicating a novel link between the complement system and cellular immunity. Also, CD46 interacts with at least seven human pathogens and participates in reproduction/fertilization, further suggesting that dissecting its multi-faceted activities will have important clinical implications.

Anemia, Hemolytic↗

PubMed2003

Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype.

The immune system must distinguish not only between self and non-self, but also between innocuous and pathological foreign antigens to prevent unnecessary or self-destructive immune responses. Unresponsiveness to harmless antigens is established through central and peripheral processes. Whereas clonal deletion and anergy are mechanisms of peripheral tolerance, active suppression by T-regulatory 1 (Tr1) cells has emerged as an essential factor in the control of autoreactive cells. Tr1 cells are CD4+ T lymphocytes that are defined by their production of interleukin 10 (IL-10) and suppression of T-helper cells; however, the physiological conditions underlying Tr1 differentiation are unknown. Here we show that co-engagement of CD3 and the complement regulator CD46 in the presence of IL-2 induces a Tr1-specific cytokine phenotype in human CD4+ T cells. These CD3/CD46-stimulated IL-10-producing CD4+ cells proliferate strongly, suppress activation of bystander T cells and acquire a memory phenotype. Our findings identify an endogenous receptor-mediated event that drives Tr1 differentiation and suggest that the complement system has a previously unappreciated role in T-cell-mediated immunity and tolerance.

Antigens, CD↗

PubMed2002

Characterization of human membrane cofactor protein (MCP; CD46) on spermatozoa.

Membrane cofactor protein (MCP; CD46) is a complement regulator widely expressed as four isoforms that arise via alternative splicing. On human spermatozoa, MCP is expressed on the inner acrosomal membrane and alterations of spermatozoa MCP may be associated with infertility. In rodents, expression of MCP is largely restricted to the testes. MCP on human spermatozoa has a unique M(r) pattern that we have investigated. We also characterized MCP expression in mice transgenic (tg) for human MCP. Human MCP expression in the tg mice mimics the human pattern in that it is located on the inner acrosomal membrane and has a faster M(r) than MCP expressed elsewhere. Sequencing of RT-PCR products from the testis indicates that there is not a unique male reproductive tissue specific cytoplasmic tail. Instead, human spermatozoa express MCP bearing cytoplasmic tail two, which is also utilized in most other tissues and contains several signaling motifs. Further, using N-glycosidases, we demonstrate that the unique lower molecular weight of MCP on spermatozoa is secondary to a modification in the N-linked sugars. Specifically, as the spermatozoa mature, but before they reach the epididymis, the three N-linked sugars of MCP are trimmed to less complex structures. While the purpose of this deglycosylation is unknown, we propose that it is a common feature of proteins expressed on the plasma and inner acrosomal membranes of spermatozoa and hypothesize that it is a spermatozoa specific event critical for facilitating sperm-egg interactions.

Animals↗