Signals through CD8 or CD4 can induce commitment to the CD4 lineage in the thymus

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CD4+CD8+ thymocytes are either positively selected and subsequently mature to CD4 single positive (SP) or CD8 SP T cells, or they die by apoptosis due to neglect or negative selection. This clonal selection is essential for establishing a functional self-restricted T cell repertoire. Intracellular signals through the three known mitogen-activated protein (MAP) kinase pathways have been shown to selectively guide positive or negative selection. Whereas the c-Jun N-terminal kinase and p38 MAP kinase regulate negative selection of thymocytes, the extracellular signal-regulated kinase (ERK) pathway is required for positive selection and T cell lineage commitment. In this paper, we show that the MAP/ERK kinase (MEK)-ERK pathway is also involved in negative selection. Thymocytes from newborn TCR transgenic mice were cultured with TCR/CD3ε-specific Abs or TCR-specific agonist peptides to induce negative selection. In the presence of the MEK-specific pharmacological inhibitors PD98059 or UO126, cell recovery was enhanced and deletion of DP thymocytes was drastically reduced. Furthermore, development of CD4 SP T cells was blocked, but differentiation of mature CD8 SP T cells proceeded in the presence of agonist peptides when MEK activity was blocked. Thus, our data indicate that the outcome between positively and negatively selecting signals is critically dependent on MEK activity.

Section: Discussionsupporting

confidence: 92%

MEK Activity Regulates Negative Selection of Immature CD4+CD8+ Thymocytes

Bommhardt¹,

Scheuring²,

Bickel³

et al. 2000

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“…According to the current models of selection, strength and duration of TCR-mediated signaling determine lineage commitment or efficiency of selection of CD4 ϩ or CD8 ϩ T cells (47,54), whereby strong or long-lasting signals favor CD4 and weaker or short signals CD8 maturation. In particular, experiments using thymic organ culture (55,56) and Lck transgenic mice (57,58) have demonstrated that relatively small alterations in intrathymic Lck activity can significantly affect the CD4/CD8 lineage decision. Likewise, several studies using genetically modified mice and in vitro differentiation systems have shown that the strength/duration of Raf-Mek-Erk signaling regulates positive selection, lineage commitment, and negative selection (47).…”

Section: Discussionmentioning

confidence: 99%

Constitutively Active Protein Kinase B Enhances Lck and Erk Activities and Influences Thymocyte Selection and Activation

Patra

Scheuring

et al. 2003

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Protein kinase B (PKB), a serine threonine kinase is critically involved in cellular proliferation and survival. To characterize its role in T cell development in vivo, we have analyzed transgenic mice that express a membrane-targeted constitutively active version of PKB (myr PKB) in thymocytes and peripheral T cells. We report that myr PKB renders proliferative responses of thymocytes more sensitive to TCR signals by increased and sustained activation of Src kinase Lck and the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. In addition, the proliferative response of myr PKB T cells is relatively independent of calcium mobilization and calcineurin activity. We also find that myr PKB enhances phosphorylation of glycogen synthase kinase 3, a negative regulator of NFAT and T cell activation, and the recruitment of the adapter protein Cbl-c. Interestingly, we demonstrate that upon TCR/CD3 stimulation of wild-type T cells PKB is translocated into lipid rafts, adding a new role for PKB in TCR-initiated signalosome formation in T cell activation. Localization of transgenic PKB in lipid rafts could contribute to the higher TCR sensitivity of myr PKB thymocytes which is reflected in an increase in positive selection toward the CD4 lineage and variable effects on negative selection depending on the model system analyzed. Thus, our observations clearly indicate a cross-talk between PKB and important signaling molecules downstream of TCR that modulate the thresholds of thymocyte selection and T cell activation.

“…Other investigators have also reported that anti-TCR Ab restores the generation of CD4 ϩ CD8 Ϫ thymocytes in class II MHC-deficient FTOC (15,16). However, the in vitro culture system of FTOC did not allow us to examine whether the newly generated CD4 ϩ CD8 Ϫ thymocytes could emigrate the thymus to supply CD4 T cells in the periphery.…”

Section: Ifferentiation Of Immature Cd4mentioning

confidence: 97%

In Vivo Treatment of Class II MHC-Deficient Mice with Anti-TCR Antibody Restores the Generation of Circulating CD4 T Cells and Optimal Architecture of Thymic Medulla

Nasreen

Ueno

Saito

et al. 2003

TCR ligation by the self-peptide-associated MHC molecules is essential for T cell development in the thymus, so that class II MHC-deficient mice do not generate CD4+CD8− T cells. The present results show that the administration of anti-TCR mAb into class II MHC-deficient mice restores the generation of CD4+CD8− T cells in vivo. The CD4 T cells were recovered in the thymus, peripheral blood, and the spleen, indicating that the anti-TCR treatment is sufficient for peripheral supply of newly generated CD4 T cells. Unlike peripheral CD4 T cells that disappeared within 5 wk after the treatment, CD4+CD8− thymocytes remained undiminished even after 5 wk, suggesting that CD4 T cells in the thymus are maintained separately from circulating CD4 T cells and even without class II MHC molecules. It was also found that the mass of medullary region in the thymus, which was reduced in class II MHC-deficient mice, was restored by the anti-TCR administration, suggesting that the medulla for CD4+CD8− thymocytes is formed independently of the medulla for CD4−CD8+ thymocytes. These results indicate that in vivo anti-TCR treatment in class II MHC-deficient mice restores the generation of circulating CD4 T cells and optimal formation of the medulla in the thymus, suggesting that anti-TCR Ab may be useful for clinical treatment of class II MHC deficiencies.