Neuroinflammation by cytotoxic T-lymphocytes impairs retrograde axonal transport in an oligodendrocyte mutant mouse

Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage

Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the α3 domain of MHC I molecules

THE α1 and α2 domains of major histocompatibility complex (MHC) class I molecules function in the binding and presentation of foreign peptides to the T-cell antigen receptor and control both negative and positive selection of the T-cell repertoire. Although the α3 domain of class I is not involved in peptide binding, it does interact with the T-cell accessory molecule, CDS. CDS is important in the selection of T cells as anti-CDS antibody injected into perinatal mice interfers with this process. We previously used a hybrid class I molecule with the α1/α2 domains from L^d and the α3 domain from Q7^b and showed that this molecule binds an L^d-restricted peptide but does not interact with CD8-dependent cytotoxic T lymphocytes. Expression of this molecule in transgenic mice fails to negatively select a subpopulation of anti-L^d cytotoxic T lymphocytes. In addition, positive selection of virus-specific L^d-restricted cytotoxic T lymphocytes does not occur. We conclude that besides the α1/α2 domains of class I, the α3 domain plays an important part in both positive and negative selection of antigen-specific cells

Generation of virus-specific cytotoxic T cells in vitro I. Induction conditions of primary and secondary Sendai virus-specific cytotoxic T cells

H-2-restricted cytotoxic T cells specific for Sendai virus were generated in vitro in a primary response from normal mouse lymphocytes cultured in the presence of infective as well as inactivated Sendai virus. Antigen-presenting cells of different origin, including T cells, were found to be effective stimulators. Antibodies to Sendai virus were shown to inhibit the activation of specific precursor killer cells when added to cultures before, but not after, the addition of viral antigen. Data obtained by Lyt phenotyping, revealed that precursor killer cells specific for Sendai virus reside in the Lyt-2,3+ T cell population and that Lyt-l,2,3+ T cells are not required for the generation of cytotoxic lymphocytes. Different activation kinetics were demonstrated for primary and secondary antiviral cytotoxic responses, and the analysis of the proliferation and stimulation requirements suggests qualitative differences

Methods and compositions for stimulating T-lymphocytes

Disclosed are methods, compositions, antibodies, and therapeutic kits for use in stimulating cytotoxic T-lymphocytes and generating immune responses against epitopes of protooncogenes. Novel peptides are described which have been shown to stimulate cytotoxic T-lymphocytes, and act as antigens in generation of oncogenic epitope-recognizing antibodies. Methods are disclosed for use in treating various proliferative disorders, and diagnosing HER-2/neu-containing cells; also disclosed are therapeutic kits useful in the treatment of cancer and production of potential anti-cancer vaccines.Board of Regents, University of Texas Syste

HLA-Associated viral mutations are common in human immunodeficiency virus type 1 elite controllers

Elite controllers (EC) of human immunodeficiency virus type 1 (HTV-1) maintain viremia below the limit of detection without antiretroviral treatment. Virus-specific cytotoxic CD8+ T lymphocytes are believed to play a crucial role in viral containment, but the degree of immune imprinting and compensatory mutations in EC is unclear. We obtained plasma gag, pol, and nef sequences from HLA-diverse subjects and found that 30 to 40% of the predefined HLA-associated polymorphic sites show evidence of immune selection pressure in EC., compared to approximately 50% of the sites in chronic progressors. These data indicate ongoing viral replication and escape from cytotoxic T lymphocytes are present even in strictly controlled HTV-1 infection

Influence of the age and disease colorectal in immunity cutaneous pericolostomic

Objective: describe the immunological response in the dermal layer of the peri-colostomic region. Method: Forty-one patients with colostomies realized over eight weeks previously, were included. For the analysis of the immunocellular response in the peri-colostomic dermal region, the values of Pan T lymphocytes, T lymphocytes - helper, T lymphocytes - cytotoxic, lymphocytes B, T lymphocytes - Natural Killer and macrophages. Results: Analysis of the immuno-cellular response showed that both in the benign colorectal disease as well as in the malignant one number of Pan T lymphocytes, T lymphocytes - helper, T lymphocytes - cytotoxic and macrophages were statistically significant relationship major than B Lymphocytes and T lymphocytes - Natural Killer. Analysis of the immuno-cellular response based on age, demonstrated that both the adult age bracket as well as the geriatric one, displayed a major number of Pan T lymphocytes, T lymphocytes - helper and macrophages, with their numerical value significantly than the B lymphocytes and the T lymphocytes - Natural Killer, beyond the T lymphocytes - cytotoxic with the B lymphocytes and the T lymphocytes - Natural Killer in the adult age. Conclusion: The presence of a colostomy promotes the development of an immuno-cellular response in the dermal layer of the peri-colostomy region that is composed of a major number of Pan T lymphocytes, T lymphocytes - helper, T lymphocytes - cytotoxic and macrophages.Objetivo: Caracterizar a resposta imunológica presente na camada dérmica da região peri-colostômica. Método: Foram incluídos quarenta e um doentes, portadores de colostomias realizadas há mais de oito semanas. Na determinação imuno-histoquímica foram avaliados os linfócitos Pan T, linfócito T - auxiliar, linfócito T - citotóxico, linfócito B, linfócito T - Natural Killer e os macrófagos. Resultados: Na análise da resposta imune-celular, independente da doença colorretal, foi observada uma relação com significância estatística quando se comparou os valores dos linfócitos Pan T, linfócito T - auxiliar, linfócito T - citotóxico e dos macrófagos, com as do linfócito B, linfócito T - Natural Killer. Na análise da resposta imune-celular de acordo com a idade, observou-se uma significância estatística da relação do linfócito Pan T, linfócito T - auxiliar e do macrófago, com as do linfócito B, linfócito T - Natural Killer, em ambas as faixas etárias, além do linfócito T - citotóxico com as do linfócito B, linfócito T - Natural Killer na faixa etária adulta. Conclusão: A presença da colostomia determina o desenvolvimento de uma resposta imune-celular na camada dérmica da região peri-colostômica, sendo composta em maior número pelo linfócito Pan T, linfócito T - auxiliar, linfócito T - citotóxico e macrófagos.Universidade de Taubaté Departamento de Medicina ASBCPUniversidade Federal de São Paulo (UNIFESP) Departamento de Cirurgia TSBCPUniversidade Federal de São Paulo (UNIFESP) Departamento de PatologiaUniversidade Federal de São Paulo (UNIFESP) Departamento de CirurgiaUniversidade de Taubaté Departamento de MedicinaUNIFESP, Depto. de Cirurgia TSBCPUNIFESP, Depto. de PatologiaUNIFESP, Depto. de CirurgiaSciEL

Target cell-dependent T cell-mediated lysis of vaccinia virus-infected cells

Vaccinia virus specific cytotoxicity against infected target cells was observed in vitro. Spleen lymphocytes from normal and immunized mice of the inbred strains C3H and DBA/2 were incubated with vaccinia virus-infected and non-infected 51Cr-labeled mastocytoma P-815-X2 cells and L-929 fibroblasts, which were used as targets. Cytotoxic lymphocytes could be isolated from the mice as early as 2 days after infection with vaccinia virus. The highest cytotoxic effect was obtained with lymphocytes taken 6 days after infection. The degree of lysi was correlated with the ratio of immune lymphocytes to target cells. Specific blocking of target cell lysis resulted after addition of anti-vaccinia antibody from different sources. The effector cells could be characterized as T cells by elimination of macrophages and B cells. Target cell killing was only possible in a syngeneic system; allogeneic infected target cells were not lysed significantly

Lysis mediated by T cells and restricted by H-2 antigen of target cells infected with vaccinia virus

VARIOUS virus infections lead to the formation of cytotoxic lymphocytes (CL), which are capable of killing virus-infected target cells1−4. Specific lysis of target cells infected with 51Cr-labelled vaccinia virus could be observed when investigating the cell-mediated cytotoxic reaction to vaccinia virus5; the CL could be characterised as a T cell. The sensitised lymphocytes from C3H mice could only kill syngeneic L929 cells infected with vaccinia virus, whereas lysis by sensitised lymphocytes derived from DBA/2 mice was restricted to the syngeneic infected mastocytoma P815X2 cells. In the lymphocytic choriomeningitis infection the target cell lysis was shown to be restricted by H-2 antigen6. We report here experiments with primary fibroblasts of the mouse strains C3H, DBA/2 and the (C3H DBA/2)F1 generation were designed to affirm that the effector phase of virus-specific lysis of target cells mediated by T cells is restricted by H-2 antigen even in the vaccinia virus infection. Further experiments with H-2 alloantisera were performed to indicate the close local relationship between H-2 antigens and viral surface antigens

Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells

A critical determinant of tumor eradication by adoptive immunotherapy is the tumor associated antigen recognized by cytotoxic T lymphocytes. Here the authors generate ex vivo autologous cytotoxic T lymphocytes by exposure to antigens induced by DNA demethylation and report the results of a phase 1 trial of 25 patients with recurrent glioblastoma multiforme with tumor regression in three patients

Perforin, granzyme B, and FasL expression by peripheral blood T lymphocytes in emphysema

<p>Abstract</p> <p>Background</p> <p>It is generally accepted that emphysematous lungs are characterized by an increase in the numbers of neutrophils, macrophages, and CD8⁺T lymphocytes, the lasts having increased cytotoxic activity. Because systemic inflammation is also a component of emphysema, we hypothesize that peripheral CD8⁺T lymphocytes of emphysematous smokers who show evidence of systemic inflammation will have higher expression of cytotoxic molecules.</p> <p>Methods</p> <p>We assessed parameters of systemic inflammation in normal individuals (smokers or non-smokers) and in emphysematous subjects with an active smoking history by measuring serum interleukine-6, C-reactive protein, and tumor necrosis factor. Expression of perforin, granzyme B, and FasL protein by CD8⁺T lymphocytes, CD4⁺T lymphocytes, and natural killer cells were assessed by flow cytometry while perforin, granzyme B, and FasL mRNA expression were measured on purified systemic CD8⁺T lymphocytes by real-time PCR.</p> <p>Results</p> <p>Emphysematous smokers had higher levels of serum interleukine-6 than normal subjects. Even with the presence of systemic inflammation in emphysematous smokers, the percentage of peripheral CD8⁺T lymphocytes, CD4⁺T lymphocytes, and NK cells expressing perforin and granzyme B protein was not different between the three groups.</p> <p>Conclusion</p> <p>Despite evidence of systemic inflammation, peripheral T lymphocytes of emphysematous smokers did not show higher levels of cytotoxic markers, suggesting that increase of activated T lymphocytes in the emphysematous lung may be due to either activation in the lung or specific peripheral recruitment.</p