Stephanie Schulz

The guanylate cyclase/receptor family of proteins.

Guanylate cyclase, which catalyzes the formation of cGMP from GTP, exists in both the soluble and particulate fractions of cells. At least two different cellular compartments for the particulate enzyme exist: the plasma membrane and cytoskeleton. The enzyme form found in the soluble fraction is a heterodimer that can be regulated by free radicals and nitrovasodilators, whereas the membrane form exists as a single‐chain polypeptide that can be regulated by various peptides. These peptides include resact and speract obtained from eggs and atrial natriuretic peptides (ANP). The species of guanylate cyclase present in cytoskeletal fractions resists solubilization with non‐ionic detergents; its structural properties are not yet known. cDNAs encoding the membrane form of guanylate cyclase have been isolated from different tissues and species, and in all cases the DNA sequences predict a protein containing a single transmembrane domain. The carboxyl (intracellular) domain is highly conserved from sea urchins through mammals, whereas the extracellular domain (amino terminus) varies considerably. The predicted amino acid sequences demonstrate that the membrane form of guanylate cyclase is a member of a diverse and complex family of proteins that includes a low molecular weight ANP receptor, protein kinases, and the cytoplasmic form of guanylate cyclase. cDNA encoding a membrane form of the enzyme from mammalian tissues has been expressed in cultured cells, and the expressed guanylate cyclase specifically binds ANP and is activated by ANP. The membrane form of guanylate cyclase, then, serves as a cell surface receptor, representing the first recognized protein to directly catalyze formation of a low molecular weight second messenger in response to ligand binding.—Schulz, S.; Chinkers, M.; Garbers, D. L. The guanylate cyclase/receptor family of proteins. FASEB J. 3: 2026‐2035; 1989.

Self-tolerance eliminates CD4+ T, but not CD8+ T or B, cells corrupting cancer immunotherapy

Self‐tolerance, presumably through lineage‐unbiased elimination of self‐antigen‐specific lymphocytes (CD4+ T, CD8+ T, and B cells), creates a formidable barrier to cancer immunotherapy. In contrast to this prevailing paradigm, we demonstrate that for some antigens, self‐tolerance reflects selective elimination of antigen‐specific CD4+ T cells, but preservation of CD8+ T‐ and B‐cell populations. In mice, antigen‐specific CD4+ T‐cell tolerance restricted CD8+ T‐ and B‐cell responses targeting the endogenous self‐antigen guanylyl cyclase c (GUCY2C) in colorectal cancer. Although selective CD4+ T‐cell tolerance blocked GUCY2C‐specific antitumor immunity and memory responses, it offered a unique solution to the inefficacy of GUCY2C vaccines through recruitment of self‐antigen‐independent CD4+ T‐cell help. Incorporating CD4+ T‐cell epitopes from foreign antigens into vaccines against GUCY2C reconstituted CD4+ T‐cell help, revealing the latent functional capacity of GUCY2C‐specific CD8+ T‐ and B‐cell pools, producing durable antitumor immunity without autoimmunity. Incorporating CD4+ T‐cell epitopes from foreign antigens into vaccines targeting self‐antigens in melanoma (Trp2) and breast cancer (Her2) produced similar results, suggesting selective CD4+ T‐cell tolerance underlies ineffective vaccination against many cancer antigens. Thus, identification of self‐antigens characterized by selective CD4+ T‐cell tolerance and abrogation of such tolerance through self‐antigen‐independent T‐cell help is essential for future immunotherapeutics.

Selective antigen-specific CD4+T-cell, but not CD8+T- or B-cell, tolerance corrupts cancer immunotherapy: Cellular immune response

Self‐tolerance, presumably through lineage‐unbiased elimination of self‐antigen‐specific lymphocytes (CD4+ T, CD8+ T, and B cells), creates a formidable barrier to cancer immunotherapy. In contrast to this prevailing paradigm, we demonstrate that for some antigens, self‐tolerance reflects selective elimination of antigen‐specific CD4+ T cells, but preservation of CD8+ T‐ and B‐cell populations. In mice, antigen‐specific CD4+ T‐cell tolerance restricted CD8+ T‐ and B‐cell responses targeting the endogenous self‐antigen guanylyl cyclase c (GUCY2C) in colorectal cancer. Although selective CD4+ T‐cell tolerance blocked GUCY2C‐specific antitumor immunity and memory responses, it offered a unique solution to the inefficacy of GUCY2C vaccines through recruitment of self‐antigen‐independent CD4+ T‐cell help. Incorporating CD4+ T‐cell epitopes from foreign antigens into vaccines against GUCY2C reconstituted CD4+ T‐cell help, revealing the latent functional capacity of GUCY2C‐specific CD8+ T‐ and B‐cell pools, producing durable antitumor immunity without autoimmunity. Incorporating CD4+ T‐cell epitopes from foreign antigens into vaccines targeting self‐antigens in melanoma (Trp2) and breast cancer (Her2) produced similar results, suggesting selective CD4+ T‐cell tolerance underlies ineffective vaccination against many cancer antigens. Thus, identification of self‐antigens characterized by selective CD4+ T‐cell tolerance and abrogation of such tolerance through self‐antigen‐independent T‐cell help is essential for future immunotherapeutics.

GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor))

Review on GUCY2C (guanylate cyclase 2C (heat stable enterotoxin receptor)), with data on DNA, on the protein encoded, and where the gene is implicated.