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 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 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.

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.

scholarly journals Self–class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels

2009 ◽  
Vol 206 (10) ◽  
pp. 2253-2269 ◽  
Author(s):  
Kensuke Takada ◽  
Stephen C. Jameson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Class I ◽  
Class I Mhc ◽  
Mhc Molecules ◽  
T Cell Survival ◽  
And Function

Previous studies have suggested that naive CD8 T cells require self-peptide–major histocompatability complex (MHC) complexes for maintenance. However, interpretation of such studies is complicated because of the involvement of lymphopenic animals, as lymphopenia drastically alters naive T cell homeostasis and function. In this study, we explored naive CD8 T cell survival and function in nonlymphopenic conditions by using bone marrow chimeric donors and hosts in which class I MHC expression is absent or limited to radiosensitive versus radioresistant cells. We found that long-term survival of naive CD8 T cells (but not CD4 T cells) was impaired in the absence of class I MHC. However, distinct from this effect, class I MHC deprivation also enhanced naive CD8 T cell responsiveness to low-affinity (but not high-affinity) peptide–MHC ligands. We found that this improved sensitivity was a consequence of up-regulated CD8 levels, which was mediated through a transcriptional mechanism. Hence, our data suggest that, in a nonlymphopenic setting, self-class I MHC molecules support CD8 T cell survival, but that these interactions also attenuate naive T cell sensitivity by dynamic tuning of CD8 levels.

CLASS I MHC MEDIATES PROGRAMMED CELL DEATH IN HUMAN LYMPHOID CELLS1

1997 ◽  
Vol 64 (1) ◽  
pp. 140-146 ◽  
Author(s):  
E. Steve Woodle ◽  
Douglas M. Smith ◽  
Naxin Zhou
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Class I ◽  
Class I Mhc

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 Peter Doherty, Nobel Laureate: Questions and Reflections Concerning MHC Restriction and other Fruits of a Life of Biomedical Erudition

2018 ◽  
Vol 3 (2) ◽  
pp. 224 ◽  
Author(s):  
Neil S. Greenspan
Keyword(s):  
T Cells ◽  
Nobel Prize ◽  
Cytotoxic T Cells ◽  
Nobel Laureate ◽  
Class I ◽  
Target Cells ◽  
Major Advance ◽  
Class I Mhc ◽  
Mhc Restriction ◽  
Mhc Molecules

In 1974, Peter Doherty and Rolf Zinkernagel published a landmark article in Nature [1] that described the ability of lymphocytic choriomeningitis virus (LCMV)-specific cytotoxic T cells to lyse LCMV-infected, 51Cr-labeled target cells if the target cells shared class I major histocompatibility complex (MHC) molecules with these T cells. Surprisingly, infected and labeled target cells with disparate class I MHC molecules were not lysed. This phenomenon, which came to be known as “MHC restriction,” was a major advance in our understanding of the way in which T cells recognize antigen and was ultimately the basis for the awarding of the 1996 Nobel Prize in Physiology or Medicine to Peter Doherty and Rolf Zinkernagel. Readers interested in more information on Dr. Doherty or on MHC restriction are referred to the relevant pages of the Nobel Prize website [2].

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