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Biomedical subjects

C A Janeway

Publications and source records attributed to C A Janeway.

At least 289 records · Page 16Linked to original sources
PubMed1976

The specificity of T lymphocyte responses to chemically defined antigens.

A system is described that allows the definition of T cell receptor specificity with some precision. It involves immunization of guinea pigs with hapten coupled to mycobacteria. The T cells of such animals respond to many but not all carriers modified by that hapten. Such T cells recognize neither hapten nor carrier alone, but rather determinants involving both the hapten and the carrier. No evidence for hapten-specific T cells was found. A model of the antigen binding site of the T cell receptor emerged from these experiments. According to this model, the T cell receptor consists of a single site of relatively large extent involving multiple subsites which are of low and roughly equal affinity. Thus, the haptenic group is not immunodominant for T cells as it is for B cells and for anti-hapten antibody. This suggests that the antigen binding receptor on T cells differs in some fundamental way from that on B cells. It is proposed that antigen recognition by T cells is mediated by an immunoglobulin heavy chain variable region that is not paired with an immunoglobulin light chain variable region.

Animals↗
PubMed1975

The specificity of cellular immune responses in guinea pigs. I. T cells specific for 2,4-dinitrophenyl-o-tyrosyl residues.

Guinea pigs immunized with the hapten 2,4-dinitrophenyl (DNP) coupled directly to Mycobacterium tuberculosis of strain H37Ra (DNP-H37) show a variety of cell-mediated immune responses to DNP coupled to protein carriers. The cells responsible for this specific response are thought to be T lymphocytes for the following reasons: Guinea pigs immunized with DNP-H37 displayed delayed hypersensitivity reactions to several DNP-proteins and contact sensitivity to dinitrofluorobenzene. Peritoneal exudate lymphocytes (PELs) obtained from DNP-H37 immune animals respond to DNP-proteins with DNA systhesis and cause inhibition of macrophage migration. PELs are highly enriched in T lymphocytes and contain few immunoglobulin-bearing cells. Further depletion of immunoglobulin-bearing cells from this population does not diminish the in vitro proliferative response to antigen. Nitrophenyl conjugates of proteins lacking a paranitro group stimulated DNA synthesis poorly or not at all, indicating the importance of the paranitro group of DNP in antigen recognition by T cells in this system. In this respect, the specificity of T cells resembles that of DNP-specific antibody from the same animals. On the other hand, DNP conjugates of copolymers of glutamic acid and lysine and DNP conjugated to proteins via an interposed beta-alanyl-glycyl-glycyl spacer failed to stimulate DNA synthesis, although such compounds bind very efficiently to anti-DNP antibody. By contrast, DNP conjugates of synthetic polypeptide carriers containing as little as 7% tyrosine strongly stimulated DNA synthesis in DNP-H37 immune PELs. That the determinant responsible for this stimulation was DNP coupled to the hydroxyl group of tyrosine was shown by selective removal of DNP from tyrosine by thiolysis with 2-mercaptoethanol, which abolished their ability to stimulate T cells.

Albumins↗
PubMed1975

The role of thymus-derived lymphocytes in an antibody-mediated hapten-specific helper effect.

The cellular basis of the antibody-mediated, hapten-specific anti-idiotype antibody response of CBA/J mice to a hapten conjugate of the BALB/c myeloma protein LPC-1 was examined. Previous studies have shown that anti-idiotype antibody is produced if the mice are given anti-2,4-dinitrophenyl (DNP) antibody and then immunized with DNP-LPC-1; immunization with DNP-LPC-1 or LPC-1 alone does not lead to the production of this antibody. In the present experiments, mice depleted of thymus-derived lymphocytes by two different techniques failed to make anti-idiotype antibody after transfer of anti-DNP antibody and immunization with DNP-LPC-1. However, thymus-deprived mice given anti-DNP antibody and reconstituted with thymus-derived spleen cells did make anti-idiotype antibody in response to DNP-LPC-1. Thymocytes could not reconstitute such mice for this response. The possible mechanisms for this hapten-specific, antibody-mediated, T cell-dependent helper effect are discussed. It is felt that such helper effects represent an alternate pathway to conventional specific T cell-mediated cooperation. Further examples of antibody-mediated helper effects which support this hypothesis are also presented.

Animals↗
PubMed1975

Recognition of immunoglobulin idiotypes by thymus-derived lymphocytes.

The ability of thymus-derived lymphocytes (T cells) from BALB/c mice to recognize the individually specific antigenic determinants (idiotypes) of BALB/c myeloma proteins was tested. Spleen cells from donor mice immunized with a given myeloma protein greatly augmented the response of hapten-specific bone marrow-derived, thymus-independent lymphocytes (cells) to a hapten conjugate of the immunizing myeloma protein. This helper effect was specific for the myeloma protein idiotype; responses to hapten conjugates of similar myeloma proteins, bearing different idiotypic determinants, were not augmented by these spleen cells. That the helper cell is a T cell was shown by its marked sensitivity to cytolysis with an isoantiserum specific for T cells (anti-Thy-1-2) and complement. The discrimination between idiotypes by such T cells is roughly comparable to that of the antibody produced by the donors of the helper cells.

Animals↗
PubMed1975

Cellular cooperation during in vivo anti-hapten antibody responses. I. The effect of cell number on the response.

Cellular interactions in adoptive secondary anti-hapten antibody responses to the hapten 2, 4-dinitrophenyl (DNP) have been studied. It was shown that DNP-specific B cells must interact with carrier specific helper T cells to give optimal responses. Independent titration of B cell and helper cell activity in adoptive anti-DNP antibody responses gave the following results: Doubling the number of transferred B cells approximately doubled the subsequent antibody response. Doubling the number of helper cells leads to nearly 4 times as much anti-DNP antibody, measured 7 days after boosting ("premium effect"). This marked effect of helper cell number on the antibody response is thought to be due primarly to the interaction of two populations of carrier-specific cells in the helper effect, or to the interaction of two activities of a single population of helper cells, namely clone activation and clone expansion. Only a very small proportion of the premium effect given by helper cells could be attributed to increases in antibody affinity.

Animals↗
PubMed1975

Cellular cooperation during in vivo anti-hapten antibody responses. II. The effect of in vivo and in vitro x-irradiation on T and B cells.

The effect of x-irradiation on T and B cells involved in an in vivo adoptive anti-hapten antibody response has been studied. In vitro x-irradiation inactivates both B cells and T cells. B cells are somewhat more sensitive than T cells to such treatment, the dose required to reduce B cell activity by 50% being about 50 R, whereas 200 R will reduce helper cell activity by 50%. By contrast, if recipient mice are primed with carrier, they develop helper activity that is totally resistant to 500 R x-irradiation within 3 days of immunization. This activity can not be transferred from irradiated, carrier-primed mice by either spleen cells or serum, although anti-carrier antibody is shown to give a modest helper effect late after boosting. However, this radioresistant helper effect can be reproduced in a cell transfer system by giving carrier-primed spleen cells to normal recipients that are then x-irradiated (500R) and given a large dose of carrier protein. Neither cells nor carrier alone will give rise to such radioresistant helper effects. Similar helper activity is occasionally observed when normal mice are irradiated 24 hr after being given helper cells, in the abscence of carrier and boosted shortly thereafter. The differences between these radioresistant helper effects, and the radiosensitivity of helper cells transferred after x-irradiation, may be related to x-ray induced changes in cell migration patterns.

Animals↗
PubMed1975

Cellular cooperation during in vivo anti-hapten antibody responses. III. The helper cell activity of activated thymocytes, of spleen cells treated with anti-theta serum, and of spleen cells from anti-thymocyte serum-treated or adult thymectomized donors.

An adoptive secondary anti-2,4-dinitrophenyl (DNP) antibody response involving T-B cell collaboration has been studied. In particular, attempts have been made to affect the unexpectedly steep log dose-response curve obtained when graded numbers of helper cells are transferred to irradiated recipients given a fixed number of B cells (premium effect). A variety of means were used to alter helper cell activity, and this activity was then measured quantitatively, as was the ability of the helper cells present after these treatments to give a premium effect. It was shown that activated T cells are approximately twice as active as spleen cells in helper activity and give a comparable premium effect. Graded doses of anti-theta serum plus complement markedly reduce the helper activity of spleen cells without affecting the premium effect given by the residual cells. Treatment of primed cell donors with limited doses of heterologous anti-mouse thymocyte serum (ATS) before transfer does not affect B cell activity, but readily inactivates helper cells, again without affecting the premium effect given by the residual cells. Adult thymectomy (ATx) of helper cell donors before priming with carrier led initially to increased helper activity relative to age-matched control donors. This increase may reflect the loss of nonspecific suppressor T cells from spleens shortly after ATx. Late after ATx, there was about a 2-fold decrease in helper activity, probably reflecting a loss of helper cell precursors. At no time was there any change in the premium effect. In view of the failure of any of the techniques used to abolish the premium effect given by helper cells in this response, it seems likely that this premium effect is due to the cooperative interaction of two very similar types of mature T cell. Alternatively, the premium effect observed here may result from the interaction of two activities of a single type of T cell which is mediated by independent factors.

Animals↗
PubMed1975

An analysis of the defective response of CBA/N mice to T-dependent antigens.

CBA/N mice fail to respond to T-independent antigens, and give a diminished response to T-dependent antigens. The cellular basis of the diminished response to T-dependent antigens in this strain was analyzed by means of adoptive transfers of various primed cell populations along with cells from the immunologically normal, histocompatible strain CBA/CaJ. CBA/N mice behaved normally as recipients and had normal levels of spleen helper cell activity. However, CBA/N spleen cells, used as a B cell source, produced only 56% as much antibody as CBA/CaJ cells. Since CBA/N mice have a relative frequency of immunoglobulin-bearing lymphocytes roughly half that of normal mice, these results suggest that CBA/N mice have a quantitative defect in spleen B cells responsive to T-dependent antigens.

Animals↗
PubMed1975

Functional heterogeneity among the T-derived lymphocytes of the mouse. IV. Nature of spontaneously induced suppressor cells.

When spleen cells are cultured for 4 days in the presence of fetal bovine serum, T-cells are generated which nonspecifically suppress the humoral responses of non-precultured cells to a variety of antigens. These T cells can be generated from both short-lived, sessile T1 cells and long-lived, recirculating T2 cells, and thus appear similar to suppressor T cells activated by concanavalin A.

Animals↗