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Biomedical subjects

P C Doherty

Publications and source records attributed to P C Doherty.

At least 271 records · Page 15Linked to original sources
PubMed1976

"Physiological interaction" does not explain the H-2 requirement for recognition of virus-infected cells by cytotoxic T cells.

B10.A (H-2Kk, H-2Dd) ectromelia-immune T cells from secondary responses in vitro were protent killers of both infected L929 (H-2Kk H-2Dk) and infected P-815 (H-2Kd, H-2Db) target cells. Specific competition with unlabelled targets showed that two separate T cell subsets were responsible for lysis of infected L929 and infected P-815 cells. One hypothesis to account for this (a form of "physiological interaction") is that T cells which kill one target e.g. infected L929) display only one out of two possible self-complementary recognition structures, in this example the H-2Kk alloantigen, not H-2Dd, whereas T cells that lyse infected P-815 targets display only H-2Dd, not H-2Kk. This hypothesis was tested and seems untenable because of the following results: A.TH (H-2Ks, H-2Dd) ectromelia-immune, secondary cytotoxic T cells which killed infected SJL/J (H-2Ks, H-2Ds) targets were themselves inactivated by pre-incubation with SJL/J cytotoxic T cells generated in one-way mixed lymphocyte reaction (MLR) against BALB/c (H-2Kd, H-2Dd). A.TL (H-2Ks, H-2Dd) ectromelia-immune secondary cytotoxic T cells which killed infected BALB/c targets were themselves inactivated by BALB/c cytotoxic T cells generated in MLR against SJL/J. Thus, virus-immune T cells which lyse infected targets by virtue of shared H-2K are also displaying H-2D alloantigen, and vice versa.

Animals↗
PubMed1976

Secondary cytotoxic cell response to lymphocytic choriomeningitis virus II. Nature and specificity of effector cells.

The method described in the previous paper was used to induce secondary responses in spleen cells from CBA/H mice, pre-primed with lymphocytic choriomeningitis (LCM) virus by culturing them with LCM-infected peritoneal cells. The cytolytic effector cells thus generated have been characterized. Effector cells were sensitive to treatment with anti-theta ascitic fluid and complement. Separation procedures based on rosetting of certain categories of lymphocytes with sheep red cells through an Isopaque-Ficoll gradient indicated that effector cells lacked surface immunoglobulin and generally did not bear Fc receptors. Cytolytic activity was restricted by the H-2 gene complex. Killing had single-hit characteristics. All these results suggested that the cells from memory cultures mediating cytolysis were T cells. There was evidence for two T cell subsets, a major subpopulation directed against antigens on infected targets and a minor one directed against antigens on uninfected, H-2-compatible targets. Specificity was present at the infected cell:memory responder and killer:target levels between LCM virus (an arenavirus) and ectromelia virus (a poxvirus).

Animals↗
PubMed1976

Specific immune lysis of paramyxovirus-infected cells by H-2-compatible thymus-derived lymphocytes.

Mice exposed to paramyxovirus (Sendai) generate specifically sensitized thymus-derived lymphocytes (T cells) which, in an in vitro 51Cr release assay, interact only with virus-infected target cells sharing strong transplantation antigens. Reciprocal exclusion of cytotoxic T-cell activity is found for Sendai virus, lymphocytic choriomeningitis virus and ectromelia virus. Immune T cells are detected as early as 3 days after intraperitoneal inoculation with a large dose of Sendai virus, and cytotoxicity is generally maximal on days 5-7. Lysis is restricted to interactions where sensitized lymphocytes and virus-infected target cells (fibroblasts, tumour cells or macrophages) are compatible at the K or the D locus of one H-2 haplotype. Identity of immune response (Ir) genes is neither sufficient nor necessary. Levels of T-cell responsiveness show some variation with H-2 type. Cytotoxic T-cell activity associated with H-2b is less than that recognized for H-2k or H-2d. These differences are, however, not obviously related to Ir gene control.

Animals↗
PubMed1976

Inflammatory process in murine lymphocytic choriomeningitis is maximal in H-2K or H-2D compatible interactions.

Capacity to transfer adoptively fatal lymphocytic choriomeningitis (LCM) to immunosuppressed, virus-infected recipients is a property of H-2 compatible, non-Ig-bearing virus-immune lymphocytes. Severe meningitis is recognized when donor and recipient share at least one allele at either H-2K or H-2D. Presence of unshared H-2 genes is not obviously inhibitory, and identity at the immune response (Ir) region of the H-2 gene complex is neither sufficient nor necessary. The same constraint applies to cytotoxic T cell activity in vitro; lymphocytes and virus-infected targets must be compatible for a minimum of one allele mapping at H-2K or H-2D. The present findings thus support the concept that populations of T cells, which are cytotoxic in vitro, also mediate inflammatory process in vivo and are a major, if not the only, effector population in murine LCM.

Animals↗
PubMed1975

A biological role for the major histocompatibility antigens.

A central function of the major histo-compatibility (H) antigens may be to signal changes in self to the immune system. Virus-induced modification of strong transplantation antigens apparently results in recognition by thymus-derived lymphocytes (T cells), with subsequent clonal expansion and immune elimination of cells bearing non-self determinants. The extreme genetic polymorphism found in the major H antigen systems of higher vertebrates may reflect evolutionary pressure exerted by this immunological surveillance mechanism.

Animals↗
PubMed1975

H-2 compatability requirement for T-cell-mediated lysis of target cells infected with lymphocytic choriomeningitis virus. Different cytotoxic T-cell specificities are associated with structures coded for in H-2K or H-2D;.

Use of syngeneic, allogeneic, F1, AND H-2 recombinatn mice has shown that animals injected with lymphocytic choriomeningitis (LCM) virus generate T cells which are cytotoxic for H-2K or H-2D compatible, but not H-2 different, virus-infected target cells. Three separate lines of evidence are presented which indicate that these immune T cells are sensitized to "altered-self," the self antigens involved being coded for in the H-2K or H-2d regions. Firstly, cytotoxic activity associated with mutuality at H-2D iy, lysis mediated by immune T cells from F1 or H-2 recombinant mice is specifically inhibited only by presence of unlabeled, virus-infected cells that are H-2 compatible with the targets. Thirdly, LCM-immune F1 and H-2 recombinant T cells inoculated into irradiated, virus-infected recipients proliferate only to kill target cells that are H-2 compatible with both the donor and the recipient. All of these experiments establish that there is a dissociation of T-cell activities between parental haplotypes in F1 mice, and between H-2K and H-2D in recombinants. It would thus seem that there are at least two specificities of tlcm-immune T cells in homozygotes, associated with either H-2K or H-2D, and four specificities in F1 hybrids. The significance of these findings, with respect both to gene duplication and to the marked polymorphism in the H-2 system, is discussed.

Animals↗
PubMed1975

H-2 compatibility is required for T-cell-mediated lysis of target cells infected with lymphocytic choriomeningitis virus.

Maximal cell-mediated lysis of targets infected with lymphocytic choriomeningitis virus occurs only within a H-2 compatible system. Syngeneic immune spleen cells are at least 100 times as effective as are allogeneic lymphocytes. Reciprocal restriction of cytotoxic T-cell activity has been shown to operative between H-2k, H-2d, and H-2b. Experiments with cogenic mice have localized the effect to the H-2 gene complex. Furthermore, the observation that lymphocytes from H-2a mice cause high specific 51Cr release from either H-2d virus-infected cells, indicates that identity at either the K or the D end of the H-2 gene complex is sufficient for this lytic interaction.

Animals↗
PubMed1975

Cortisone-resistant effector T cells in acute lymphocytic choriomeningitis and Listeria monocytogenes infection of mice.

Sensitized T cells in both lymphocytic choriomeningitis (LCM) and listeriosis are apparently unaffected by treatment of mice with cortisone acetate. Cortisone-resistant immune T cells readily transfer acute, fatal LCM or protection against L. monocytogenes infection. Treatment of recipient mice with cortisone, however, impairs T cell-dependent effector mechanisms (i.e. macrophages) in listeriosis, but has no effect on induction of LCM. Acute LCM may thus represent a T cell-mediated pathological process which does not require participation of macrophages.

Acute Disease↗
PubMed1975

Capacity of sensitized thymus-derived lymphocytes to induce fatal lymphocytic choriomeningitis is restricted by the H-2 gene complex.

Adoptive immunization of syngeneic, immunosuppressed recipients infected with lymphocytic choriomeningitis (LCM) virus causes fatal neurologic disease within 2 to 4 days of cell transfer, providing that donors are sampled when the in vitro 51-Cr release assay shows maximal specific activity of sensitized thymus-derived lymphocytes (T cells). Prior treatment of immune spleen cells with AKR anti-omicron ascitic fluid and complement causes total abrogation of this in vivo activity. Fatal neurologic disease is induced only when donor and recipient share at least one set of H-2 antigenic specificities. Parent yields F1 and F1 yields parent combinations are as effective as syngeneic systems, but mice given allogeneic immune cells survive as long as controlsmdifferences at the M-locus in H-2 compatible mice do not inhibit effector activity. Homing of transferred lymphocytes to spleen is similar in syngeneic or allogeneic recipients, but only syngeneic immune cells cross the blood-cerebrospinal fluid (CSF) barrier and cause choriomeningitis. Fatal LCM, is, therefore, apparently induced by a specifically sensitized omicron-bearing cell population, activity of which is restricted by the H-2 gene complex.

Animals↗
PubMed1975

Cytotoxic T cell activity is strain-specific in outbred mice infected with lymphocytic choriomeningitis virus.

The cytotoxic T cell response in outbred mice infected with lymphocytic choriomeningitis virus (LCMV) is strain specific. The same is true for adoptive transfer of fatal LCM disease. The response of individuals within an outbred strain is completely cross-reactive, as shown by using immune lymphocytes and virus-infected macrophage targets from individual mice. Reciprocal exclusion of cytotoxic T cell activity between inbred and outbred mouse strains is the rule, the exception being one strain (H) known to have some C57BL ancestry. Immune T cells from one of 7 H mice specifically lysed LCMV-infected C57BL macrophages. Experiments with inbred mice have shown that only one allele need be shared at either the H-2K or H-2D locus for cytotoxic T cell activity to be manifest. Adoptive transfer protocols may thus be considered in outbred situations, providing that T cells are effective before allograft rejection occurs. Also, the LCMV cytotoxic T cell assay may be useful for determining the degree of H-2 variability in wild mouse populations, as novel H-2 types can be detected and mice need not be congenic.

Animals↗
PubMed1975

Quantitative studies of the growth and rejection of allogeneic tumour cells in mouse cerebrospinal fluid. Elimination in the absence of H-2 differences.

Following intracerebral (i.c.) inoculation DBA/2 (H-2d) mastocytoma cells (P815) grow to concentrations of greater than 10,000/mul in cerebrospinal fluid (CSF) of H-2 compatible BALB/c mice, but are completely eliminated from 90% of such animals within 12 days. A similar pattern occurs in allogeneic C57BL (H-2b) and random-bred WEHI mice, whereas syngeneic DBA/2 mice die within 7 days from unrestricted tumour growth. Rejection in BALB/c mice is enhanced by prior exposure to the tumour, but is severely depressed by pretreatment with cyclophosphamide. Leucocytes responsible for eliminating the mastocytoma are apparently not active against sarcoma 180 cells injected simultaneously. Subsequent to intraperitoneal inoculation with mastocytoma cells both BALB/c and C57BL mice generate significant cytotoxic activity in spleen, as measured by an in vitro 51Cr release assay. Cytolysis is abrogated by prior incubation of spleen cells with AKR anti-O ascitic fluid and complement, but not by normal AKR ascitic fluid and complement. Following i.c. exposure, however, much lower levels of cytotoxic activity are found in spleen, though specifically sensitized lymphocytes are also present in lymph nodes of the cervical chain.

Animals↗