P R Billings

Bio: P R Billings is an academic researcher from Harvard University. The author has contributed to research in topics: CTL* & Cytotoxic T cell. The author has an hindex of 9, co-authored 11 publications receiving 355 citations.

Cloning and characterization of a novel T cell activation gene.

Abstract: We have used the technique of subtractive hybridization to identify a T cell gene selectively expressed during activation via the antigen-receptor pathway. This gene, termed TCA3 (for T cell activation) encodes a mRNA which is expressed following concanavalin A (Con A) activation of T cell clones at levels of approximately 1% total poly(A)-containing mRNA. The cDNA isolate, termed TCA3.0, is 512 bases in length excluding poly(A) and encodes a predicted 92-amino acid protein having the characteristics of a secreted polypeptide of approximately 69 amino acids. The genomic organizations of TCA3 was determined for two lambda phage clones and was found to be a single copy gene containing at least three exons dispersed over less than 4.7 kb. The temporal appearance of TCA3 mRNA in response to several activating agents was examined. It is not transcribed in response to interleukin 2 stimulation, but is transcribed in response to either antigen or Con A stimulation and can be detected as early as 1 hr poststimulation. Expression TCA3 in response to Con A is blocked by cyclosporin A treatment. The combined data suggest that TCA3 may represent a new lymphokine.

Clustering of cytokine genes on mouse chromosome 11.

Abstract: The presence of positionally conserved amino acid residues suggests that the mouse proteins TCA3, P500, MIP1-alpha, MIP1-beta, and JE are members of a single gene family. These proteins are activation specific and can be expressed by both myeloid and lymphoid cells. MIP1-alpha/MIP1-beta and MCAF (the putative human homologue of JE) act as chemotactic and activating agents for neutrophils and macrophages, respectively. The functions of TCA3 and P500 are unknown. We have used interspecies somatic cell hybrids and recombinant inbred mouse strains to show that the genes encoding TCA3, MIP1-alpha, MIP1-beta, and JE (provisionally termed Tca3, Mip-1a, Mip-1b, and Sigje, respectively) map as a cluster on the distal portion of mouse chromosome 11 near the Hox-2 gene complex. DNA sequence analysis indicates that the P500 and TCA3 proteins are encoded by alternative splicing products of one genomic gene. Additionally, the genes encoding TCA3 and JE are found to be strikingly similar with respect to the positions of intron-exon boundaries. Together, these data support the model that the cytokines TCA3, P500, MIP1-alpha, MIP1-beta, and JE are encoded by a single cluster of related genes. The gene encoding IL-5 (Il-5), which acts as a T cell-replacing factor, a B cell growth factor, and an eosinophil differentiation factor, is also mapped to mouse chromosome 11.Il-5 maps approximately 25 cM proximal to the Tca-3 gene and appears tightly linked to a previously described gene cluster that includes Il-3, Il-4, and Csfgm. We discuss the potential relevance of the two cytokine gene clusters described here with particular attention to specific human hematologic malignancies associated with chromosomal aberrations at corresponding locations on human chromosomes 5 and 17.

Cytotoxic T lymphocytes specific for I region determinants do not require interactions with H-2K or D gene products

Abstract: Gene products coded for by the major hisocompatibility complex (MHC) can serve as target antigens for cytotoxic T lymphocytes (CTL) (1). A variety of test systems are available which have yielded information consistently reinforcing the importance of this complex of genes in the generation and effector phases of the cytotoxic immune response. Originally, it was shown that allogeneically-induced CTL had specificity primarily for the products of the K and D loci of the mouse H-2 complex (2). More recently this has also been found to be the case for xenogeneic immunizations (3,4). Additional examples of T cell-mediated lysis have been reported involving viral-infected or chemically- modified syngeneic stimulating and target cells in which homology at H-2K or H-2D was required between the responding and target cells for appreciable lysis to occur (5-7). Moreover, CTL specific for minor histocompatability antigens are able to lyse only target cells bearing these membrane antigens and sharing a common H-2K or H2-D gene product with the effector (8,9). Two hypotheses have been proposed to explain the requirement for H-2 identity between effector and targets in these systems. CTL may recognize new antigenic determinants created by the interaction of the modifier with syngeneic K and D gene products. Alternately, a dual recognition system my exist, requiring an antigen-specific receptor as well as a second receptor with specificity for homologous H-2K or H-2D determinants (5). Neither model can be excluded at this time. The I region also contains genes coding for histocompatibility loci since animals differing at the I-A or I-C regions of the H-2 complex reject skin grafts (10-12), though less rapidly than mice differing at the H-2K or H-2D regions, Also CTL can be generated to I region determinants but less efficiently than CTL specific for H-2K or H-2D gene products (12-14). The question can therefore be raised, whether the I region minor histocompatibility loci function independently from the H-2K or H-2D loci or whether I region-specific cytolysis requires the participation of H-2K or H-2D gene products of the target cell. This communication illustrates the generation of CTL showing specificity for I region determinants in primary mixed lymphocyte cultures. Further, we demonstrate by genetic analysis and byt eh use of speficit alloantisera that CTL directed to Ia determinants (a) do not see these antigens as modifications of H-2K or H-2D gene products but as independent gene products coded for by the I region, and (b) they do not require interaction with target cells bearing the same H-2K or H-2D gene product as the effect CTL.

Genetic control of cytolytic T lymphocyte responses. III. The role of K and I region alleles on the specificity of the cytolytic T lymphocyte response to trinitrophenyl-modified syngeneic cells.

Abstract: It has previously been demonstrated that genes in the H-2K and/or I-A region control the specificity of the cytolytic T lymphocyte (CTL) response to trinitrophenyl-(TNP) modified syngeneic cells. Strains of mice bearing the k allele in the K and/or IA region do not exhibit cross-reactive lysis of TNP-modified allogeneic targets after stimulation with TNP-modified syngeneic targets. In this report we present evidence for independent roles of genes in the H-2K and I-A regions on the control of CTL specificity. One gene, mapping in the H-2K region, is expressed on the stimulator cell population, whereas the other gene maps to the I region and is expressed in the population of responding cells and need not be expressed in the stimulator cell population. Thus, we suggest that Ir genes localized to the I region may influence the response for prekiller cells to H-2K/D gene products.

Genetic control of cytolytic t-lymphocyte responses. I. Ir gene control of the specificity of cytolytic t-lymphocyte responses to trinitrophenyl-modified syngeneic cells.

Abstract: The ability of cytotoxic T lymphocytes (CTL) induced in vitro to trinitrophenyl (TNP)-modified syngeneic cells to cross-reactively lyse a TNP allogeneic spleen target varies among inbred mouse strains. The cross-reactive CTL phenotype was found to be histocompatibility 2 (H-2) linked and to be dominant in F1 hybrid mice. All strains investigated demonstrated cross-reactivity except for some strains bearing portions of the H-2k haplotype. The gene(s) controlling this response maps to the K and/or I-A region of the H-2 complex. We have termed the immune response (Ir) gene responsible for controlling the specificity of CTL induced to TNP-modified syngeneic cells Ir-X-TNP.

MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness.

Abstract: Publisher Summary This chapter focuses on the important discovery that virus-specific cytotoxic T cells are dually specific for virus and for a self cell surface antigen encoded by the major histocompatibility complex (MHC). The initial work was carried out on the lymphocytic choriomeningitis virus system but it soon became evident that the same phenomenon applied to many other viruses. In addition, the same principle has been found to hold for other antigenic systems, such as trinitrophenyl coupled to cells, minor histocompatibility antigens, and the H-Y model. Graft rejection and the need for genetically homogeneous inbred mouse strains for cancer research led to the development of transplantation immunology and immunogenetics. The result is that the gene complex coding for major transplantation antigens is one of the better understood mammalian genetic regions. Cytotoxic T-cell specificity is comparable to serological specificity. Because quantification of specificity or cross-reactivity is difficult, and because of the technical limitations of these cytotoxic T-cell assays, results are interpreted with great reservation. MHC restriction reflects the fact that the effector function of T cells is determined by the kind of Self-H recognized together with the foreign antigen on cell surfaces: K and D are receptors for lytic signals, I determinants are receptors for cell differentiation signals that are delivered antigen-specifically by T cells.

Heterogeneity of cytokine secretion patterns and functions of helper T cells.

Abstract: Publisher Summary Because cytokine functions are complex and overlapping, the development of precise, monospecific bioassays, and enzyme-linked immunosorbent assays (ELISAs) was essential, before a clear picture of T cell cytokine synthesis could be obtained. In vitro , some mast cell lines synthesize IL-4 and other cytokines of the Th2 pattern in response to cross-linking of surface IgE. Although functional evidence using mixed cell populations suggested different types of Th cells, the lack of discriminatory cell-surface markers has hampered efforts to define the different subtypes. The development of in vitro T cell clones led to the description of four types of helper T cell clones, and later, two types of Th clones (Th1 and Th2) were defined on the basis of different patterns of cytokine secretion. These patterns have been confirmed in several panels of Th clones and this is currently the most clear-cut criterion for separation of mouse Th subtypes. As the two types differ in the synthesis of many cytokines, and the cytokines have a major role in the regulation of immune responses, the two types of Th cells have markedly different functions. When injected simultaneously with antigen into the footpads of naive mice, Th1 clones cause an antigen-specific and major histocompatibility complex (MHC)-restricted inflammatory reaction that peaks at about 24 hours. Th2 clones do not produce a swelling reaction under these conditions. One of the major functions of helper T cells is to provide signals for activation, proliferation, and differentiation to B cells that have encountered an antigen. Several strategies have been employed for studying the functions of mouse Th clones in micro and for analyzing the roles of specific Th products in these functions. In spite of the clear dichotomy of mouse Th1 and Th2 clones, and the accumulating evidence for their involvement in normal immune responses, human T cells do not appear to segregate into two clear subsets. Many human T cell clones secrete both Th1and Th2 cytokines.

Contingent genetic regulatory events in T lymphocyte activation

Abstract: Interaction of antigen in the proper histocompatibility context with the T lymphocyte antigen receptor leads to an orderly series of events resulting in morphologic change, proliferation, and the acquisition of immunologic function. In most T lymphocytes two signals are required to initiate this process, one supplied by the antigen receptor and the other by accessory cells or agents that activate protein kinase C. Recently, DNA sequences have been identified that act as response elements for one or the other of the two signals, but do not respond to both signals. The fact that these sequences lie within the control regions of the same genes suggests that signals originating from separate cell membrane receptors are integrated at the level of the responsive gene. The view is put forth that these signals initiate a contingent series of gene activations that bring about proliferation and impart immunologic function.