scholarly journals Depletion of CD8+ cells in human thymic medulla results in selective immune deficiency.

1989 ◽  
Vol 170 (6) ◽  
pp. 2177-2182 ◽  
Author(s):  
C M Roifman ◽  
D Hummel ◽  
H Martinez-Valdez ◽  
P Thorner ◽  
P J Doherty ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Inbred Mice ◽  
Pneumocystis Carinii ◽  
Antigen Expression ◽  
Class I ◽  
Class I Mhc ◽  
Cd8 Cells ◽  
Mhc Antigen ◽  
Selection Of

CD8 molecules expressed on the surface of a subset of T cells participate in the selection of class I MHC antigen-restricted T cells in the thymus, and in MHC-restricted immune responses of mature class I MHC antigen-restricted T cells. Here we describe an immune-deficient patient with lack of CD8+ peripheral blood cells. The patient presented with Pneumocystis carinii pneumonia and was unable to reject an allogeneic skin graft, but had normal primary and secondary antibody responses. Examination of the patient's thymus revealed that the loss of CD8+ cells occurred during intrathymic differentiation: the patient's immature cortical thymocytes included both CD4+ and CD8+ cells while the mature medullary cells expressed the CD4 but not the CD8 protein on their surface. Northern blot and polymerase chain reaction analyses revealed the presence of CD8 alpha and beta mRNA in the patient's thymus but not in the peripheral blood. Both class I MHC antigen expression and the expressed TCR V beta repertoire are normal in this patient. These data are consistent with an impaired selection of CD8+ cells in the patient's thymus and support the role of the CD8 surface protein in thymic selection previously characterized in genetically manipulated and inbred mice.

scholarly journals Phenotypic and functional analysis of positive selection in the gamma/delta T cell lineage.

1993 ◽  
Vol 177 (4) ◽  
pp. 1061-1070 ◽  
Author(s):  
F B Wells ◽  
Y Tatsumi ◽  
J A Bluestone ◽  
S M Hedrick ◽  
J P Allison ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
Class I ◽  
Gamma Delta ◽  
Class I Mhc ◽  
General Role ◽  
Alpha Beta ◽  
Selection Of

Recent evidence suggests that T cells expressing gamma/delta antigen receptors (T cell receptor [TCR]) are subject to positive selection during development. We have shown that T cells expressing a class I major histocompatibility complex (MHC)-specific gamma/delta TCR transgene (tg) are not positively selected in class I MHC-deficient, beta 2-microglobulin (beta 2m) gene knockout mice (tg+ beta 2m-). In this report, we examine phenotypic and functional parameters of gamma/delta positive selection in this transgenic model system. TCR-gamma/delta tg+ thymocytes of mature surface phenotype (heat stable antigen-, CD5hi) were found in beta 2m+ but not in beta 2m- mice. Moreover, subsets of tg+ thymocytes with the phenotype of activated T cells (interleukin [IL]2R+, CD44hi, or Mel-14lo) were also present only in the beta 2m+ mice. Cyclosporine A, which blocks positive selection of TCR-alpha/beta T cells, also inhibited gamma/delta tg+ T cell development. These results support the idea that positive selection of TCR-gamma/delta requires active TCR-mediated signal transduction. Whereas tg+ beta 2m+ thymocytes produced IL-2 and proliferated when stimulated by alloantigen, TCR engagement of tg+ beta 2m- thymocytes by antigen induced IL-2R expression but was uncoupled from the signal transduction pathway leading to IL-2 production and autocrine proliferation. Overall, these results demonstrate significant parallels between gamma/delta and alpha/beta lineage development, and suggest a general role for TCR signaling in thymic maturation.

Role of Class-II Major Histocompatibility Complex (MHC)-Antigen–Positive Donor Leukocytes in Transfusion-Induced Alloimmunization to Donor Class-I MHC Antigens

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 690-694
Author(s):  
K.J. Kao ◽  
M.L.U. del Rosario
Keyword(s):  
Immune Response ◽  
Peripheral Blood ◽  
Class Ii ◽  
Class I ◽  
Mononuclear Leukocytes ◽  
Class I Mhc ◽  
Mhc Antigens ◽  
Mhc Molecules ◽  
Class Ii Mhc ◽  
Mhc Antigen

It has been shown that peripheral-blood mononuclear leukocytes (MNL) are responsible for transfusion-induced alloimmunization to donor major histocompatability complex (MHC) antigens. However, it is not known which subset of MNL is responsible for this immune response. Because elimination of class-II MHC antigen-positive passenger leukocytes effectively prolongs the survival of allografts, it has been hypothesized that class-II positive MNL are responsible for immunizing transfusion recipients to donor MHC antigens. To test this hypothesis, two different approaches were used. First, we compared the alloantigenicity of BALB/c mice (H-2d) peripheral blood MNL before and after depletion of class-II positive cells. CBA mice (H-2k) were used as transfusion recipients. Antibody development to donor class-I H-2 antigens was determined by flow cytometry and enzyme-linked immunoassay. After four weekly transfusions of MNL depleted for class-II positive cells, only 25% of recipient mice developed antibodies to donor H-2d antigens. In contrast, all mice transfused with control MNL became immunized. Second, we studied the alloantigenicity of peripheral MNL from C57BL/6 mice (H-2b) with homozygous deficiency of class-II MHC molecules in H-2 disparate recipient mice. After transfusions with class-II MHC molecule-deficient MNL, 0% of BALB/c, 40% of C57BR, and 25% of CBA-recipient mice developed antibodies to donor H-2b antigen. All control recipient mice were immunized. The antibody activities of the controls were also higher than those in the treatment group who became immunized. Thus, our study shows that class-II MHC antigen-positive MNL play a significant role in transfusion-induced alloimmunization to donor class-I MHC antigens. The results also support the hypothesis that direct antigen presentation by donor class-II positive MNL to the immune system of transfusion recipients is critical for the initiation of humoral immune response to donor MHC antigens.

Role of Class-II Major Histocompatibility Complex (MHC)-Antigen–Positive Donor Leukocytes in Transfusion-Induced Alloimmunization to Donor Class-I MHC Antigens

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 690-694 ◽  
Author(s):  
K.J. Kao ◽  
M.L.U. del Rosario
Keyword(s):  
Immune Response ◽  
Peripheral Blood ◽  
Class Ii ◽  
Class I ◽  
Mononuclear Leukocytes ◽  
Class I Mhc ◽  
Mhc Antigens ◽  
Mhc Molecules ◽  
Class Ii Mhc ◽  
Mhc Antigen

Abstract It has been shown that peripheral-blood mononuclear leukocytes (MNL) are responsible for transfusion-induced alloimmunization to donor major histocompatability complex (MHC) antigens. However, it is not known which subset of MNL is responsible for this immune response. Because elimination of class-II MHC antigen-positive passenger leukocytes effectively prolongs the survival of allografts, it has been hypothesized that class-II positive MNL are responsible for immunizing transfusion recipients to donor MHC antigens. To test this hypothesis, two different approaches were used. First, we compared the alloantigenicity of BALB/c mice (H-2d) peripheral blood MNL before and after depletion of class-II positive cells. CBA mice (H-2k) were used as transfusion recipients. Antibody development to donor class-I H-2 antigens was determined by flow cytometry and enzyme-linked immunoassay. After four weekly transfusions of MNL depleted for class-II positive cells, only 25% of recipient mice developed antibodies to donor H-2d antigens. In contrast, all mice transfused with control MNL became immunized. Second, we studied the alloantigenicity of peripheral MNL from C57BL/6 mice (H-2b) with homozygous deficiency of class-II MHC molecules in H-2 disparate recipient mice. After transfusions with class-II MHC molecule-deficient MNL, 0% of BALB/c, 40% of C57BR, and 25% of CBA-recipient mice developed antibodies to donor H-2b antigen. All control recipient mice were immunized. The antibody activities of the controls were also higher than those in the treatment group who became immunized. Thus, our study shows that class-II MHC antigen-positive MNL play a significant role in transfusion-induced alloimmunization to donor class-I MHC antigens. The results also support the hypothesis that direct antigen presentation by donor class-II positive MNL to the immune system of transfusion recipients is critical for the initiation of humoral immune response to donor MHC antigens.

scholarly journals T cell requirements for the rejection of renal allografts bearing an isolated class I MHC disparity.

1990 ◽  
Vol 172 (6) ◽  
pp. 1547-1557 ◽  
Author(s):  
J A Gracie ◽  
E M Bolton ◽  
C Porteous ◽  
J A Bradley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
High Responder ◽  
Class I ◽  
Donor Strain ◽  
Class I Mhc ◽  
Effector Cells ◽  
Renal Allografts ◽  
Cd8 Cells

This study has examined the cellular and humoral responses underlying the rejection of rat renal allografts bearing an isolated RT1Aa class I MHC disparity. RT1Aa disparate kidneys were rejected promptly by high responder RT1u but not by low responder RT1c recipients (median survival time 10 d and greater than 100 d, respectively). The magnitude and phenotype of the cellular infiltrate were similar in rejecting and nonrejecting RT1Aa disparate kidneys. Paradoxically, graft infiltrating cells and spleen cells from RT1u recipients showed minimal ability to lyse donor strain lymphoblasts in vitro, whereas effector cells from RT1c recipients showed modest levels of cytotoxicity. Injection of RT1u rats with MRC OX8 mAb was highly effective at selectively depleting CD8+ cells from graft recipients but had no effect in prolonging the survival of RT1Aa disparate grafts despite the complete absence of CD8+ cells from the graft infiltrate, which included numerous CD4+ T cells and macrophages. RT1u, but not RT1c, recipients mounted a strong alloantibody response against RT1Aa disparate kidneys. Immune serum obtained from RT1u recipients that had rejected a RT1Aa disparate graft was able, when injected into cyclosporin-treated RT1u recipients, to restore their ability to reject a RT1Aa, but not a third-party RT1c, kidney. These results suggest that CD8+ cells in general and CD8+ cytotoxic effector cells in particular are unnecessary for the rapid rejection of RT1Aa class I disparate kidney grafts by high responder RT1u recipients. By implication, CD4+ T cells alone are sufficient to cause prompt rejection of such grafts and they may do so by providing T cell help for the generation of alloantibody.

scholarly journals Increased frequency of T cell receptor V alpha 12.1 expression on CD8+ T cells: evidence that V alpha participates in shaping the peripheral T cell repertoire.

1991 ◽  
Vol 174 (3) ◽  
pp. 639-648 ◽  
Author(s):  
H DerSimonian ◽  
H Band ◽  
M B Brenner
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Product ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Class I ◽  
Class I Mhc ◽  
Alpha Gene

The T cell receptor repertoire has a potential for vast diversity. However, this diversity is limited by the fact that the majority of thymocytes die as the repertoire is shaped by positive and negative selection events during development. Such thymic selection affecting TCR V beta gene segment usage has been demonstrated in the mouse. However, similar data has not been forthcoming in man, and little is known about the role of the TCR alpha chain in antigen/major histocompatibility complex (MHC) recognition in any species. Here, we used a monoclonal antibody recognizing the TCR V alpha 12.1 gene product to assess the expression of this gene in the peripheral blood of man. In most individuals tested, the percentage of cells expressing V alpha 12.1 was significantly higher in CD8+ T cells than in CD4+ T cells. That the V alpha gene product itself was responsible for this increased expression in CD8+ T cells was underscored by the lack of substantial skewing of V beta usage in the V alpha 12.1-bearing T cells. Moreover, the skewed expression of V alpha 12.1 was already present at birth, indicating that it was likely to be due to a developmental process rather than the result of exposure to environmental antigens. Based on the established role for CD8 in binding to class I MHC molecules, we suggest that increased expression of V alpha 12.1 on CD8+ T cells points to a role for TCR's using V alpha 12.1 in class I MHC/Ag recognition. These results indicate that V alpha gene usage in the peripheral blood of man is not random, and they support a role for V alpha as a participant in the self-MHC recognition process that shapes the TCR repertoire.

scholarly journals Class I MHC molecules on hematopoietic cells can support intrathymic positive selection of T cell receptor transgenic T cells

1999 ◽  
Vol 96 (20) ◽  
pp. 11470-11475 ◽  
Author(s):  
J. Zerrahn ◽  
A. Volkmann ◽  
M. C. Coles ◽  
W. Held ◽  
F. A. Lemonnier ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
T Cell Receptor ◽  
Hematopoietic Cells ◽  
Cell Receptor ◽  
Class I ◽  
Class I Mhc ◽  
Mhc Molecules ◽  
Selection Of

scholarly journals Peripheral blood T cells and neutrophils from asthma patients express class-I MHC-restricted T cell-associated molecule

2014 ◽  
Vol 10 (1) ◽  
pp. 46 ◽  
Author(s):  
Carlos Ramirez-Velazquez ◽  
Nonantzin Beristain-Covarrubias ◽  
Leopoldo Guido-Bayardo ◽  
Vianney Ortiz-Navarrete
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Class I ◽  
Class I Mhc ◽  
Asthma Patients

scholarly journals Positive selection of T cells: rescue from programmed cell death and differentiation require continual engagement of the T cell receptor.

1995 ◽  
Vol 181 (6) ◽  
pp. 1975-1984 ◽  
Author(s):  
P Kisielow ◽  
A Miazek
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Positive Selection ◽  
Developmental Process ◽  
Class I ◽  
Class I Mhc ◽  
Mhc Molecules ◽  
Induction Of Differentiation ◽  
Selection Of

Positive selection of T cells is a complex developmental process generating long-lived, functionally mature CD4+CD8- and CD4-CD8+ cells from short-lived, immature CD4+CD8+ precursors. The process is initiated in the thymus by interaction of the alpha beta TCR with molecules encoded by the MHC, occurs without cell division, and involves rescue from programmed cell death (PCD), as well as induction of differentiation and maturation of selected precursors. It is unclear whether development of small, positively selected CD4+CD8+ thymocytes (characterized by up-regulated levels of TCR and CD69 molecules) depends on further interactions with MHC molecules and, if so, whether such interactions are required for survival, for maturation, or for both. The involvement of the TCR and/or CD4/CD8 coreceptors in transmitting additional signals is also unknown. We have examined these questions by analyzing survival and differentiation of early (CD4+CD8+TCRhi) and later (CD4-CD8+TCRhi) postselection stages of thymocytes from normal and bcl-2 transgenic mice expressing transgenic, class I MHC-restricted TCR, upon intrathymic transfer into recipients that lacked ligands either for both the TCR and CD8 coreceptor, or for the TCR only. The results provide direct evidence that induction of differentiation of CD4+CD8+ thymocytes by recognition of MHC molecules does not rescue them from PCD and is insufficient to activate the entire maturation program. Both processes require continual engagement of the TCR by positively selecting MHC molecules that, at least in the case of class I MHC-restricted CD4-CD8+ T cells, cannot be substituted by the engagement of coreceptor alone.

scholarly journals Modulation of  Thymic Selection by Expression of an Immediate-early Gene, Early Growth Response 1 (Egr-1)

1998 ◽  
Vol 188 (4) ◽  
pp. 715-723 ◽  
Author(s):  
Toru Miyazaki ◽  
François A. Lemonnier
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Positive Selection ◽  
Growth Response ◽  
Class I ◽  
Class I Mhc ◽  
Transgenic Mouse Line ◽  
Early Growth Response ◽  
Class Ii Mhc ◽  
Selection Of

The potential involvement of early growth response (Egr)-1, a zinc-finger transcription factor belonging to the immediate-early genes, in positive/negative selection of thymocytes has been implicated by its expression in the population of CD4+CD8+ double positive (DP) cells undergoing selection. To further investigate this possibility, transgenic mice overexpressing Egr-1 in thymocytes were bred with a transgenic mouse line expressing a T cell receptor (TCR) recognizing the H-Y male antigen in the context of H-2b class I major histocompatibility complex (MHC) molecules. In Egr-1/TCR H-Y double-transgenic mice, efficient positive selection of H-Y CD8+ T cells occurred, even in mice on either a nonselecting H-2d background or a β2-microglobulin (β2m)-deficient background in which the expression of class I MHC heavy chains is extremely low; no positive selection was observed on a Kb−/−Db−/−β2m−/− background where class I MHC expression is entirely absent. Similarly, when the Egr-1 transgene was introduced into a class II MHC–restricted TCR transgenic mouse line, Egr-1/TCR double-transgenic mice revealed increased numbers of CD4+ T cells selected by class II MHC, as well as significant numbers of CD8+ T cells selected by class I MHC (for which the transgenic TCR might have weak affinity). Thus, Egr-1 overexpression allows positive selection of thymocytes via TCR–MHC interactions of unusually low avidity, possibly by lowering the threshold of avidity required for positive selection. Supporting this possibility, increased numbers of alloreactive T cells were positively selected in Egr-1 transgenic mice, resulting in a strikingly enhanced response against allo-MHC. These results suggest that expression of Egr-1 and/or its target gene(s) may directly influence the thresholds required for thymocyte selection.

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