T cell receptor‐negative thymocytes from SCID mice can be induced to enter the CD4/CD8 differentiation pathway

Shores, Elizabeth W.; Sharrow, Susan O.; Uppenkamp, Ingeborg; Singer, Alfred

doi:10.1002/eji.1830200111

Cited by 73 publications

(45 citation statements)

References 48 publications

(10 reference statements)

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“…The latter results corresponded to our observation that addition of anti-CD3e mAb to fetal thymic organ cultures inhibited functional rearrangements of the TCR-0 locus while it accelerated induction of DP cells (11). On the other hand, other previous experiments had indicated that maturation to the DP stage could be induced in TCR-0-deficient thymorytes by transfer of syngeneic TCR+ cells (20). These latter results suggested that maturation to the DP stage did not require direct induction through TCR-O-CD3 but occurred by recruitment as soon as some TCR+ cells had been generated in the thymus.…”

supporting

confidence: 91%

“…This hypothesis predicts that all DP cells show a productive rearrangement ofthe TCR-(3 locus. On the other hand, an earlier study showed that transplantation of normal bone marrow into SCID mice gave rise to both donor-derived TCR+ thymocytes and host-derived CD4+8+TCR -SCID thymocytes (20). It was hypothesized that the presence of TCR+ thymocytes would recruit SCIDderived DN cells into the developmental process, even though these cells do not themselves show functional rearrangement of the TCR-a locus .…”

Section: Duringembryogenesis T Lineage Committed Lymphoidmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of thymocyte development through CD3. II. Expression of T cell receptor beta CD3 epsilon and maturation to the CD4+8+ stage are highly correlated in individual thymocytes.

Levelt

Carsetti

Eichmann

1993

The Journal of Experimental Medicine

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SummaryRecent studies have shown that maturation of CD4-8 -double negative (DN) thymocytes to the CD4+8+ double positive (DP) stage is dependent on expression of the T cell receptor (TCR)-a polypeptide. The exact mechanism by which the TCR-0 chain regulates this maturation step remains unknown. Previous experiments had suggested that in the presence of some TCR+ thymocytes, additional DN thymocytes not expressing a TCR-0 chain may be recruited to mature to the DP stage. The recent demonstration of an immature TCR-0-CD3 complex on early thymocytes lead to the alternative hypothesis that signal transduction through an immature TCR-CD3 complex may induce maturation to the DP stage. In the latter case, maturation to the DP stage would depend on the expression of TCR-0-CD3 in the same cell. We examined these two hypotheses by studying the expression of the intra-and extracellular CD3e, CD3', and TCR-0 polypeptides in intrathymic subpopulations during embryogenesis. CD3e and CD3' were expressed intracellularly 2 and 1 d, respectively, before intracellular expression ofthe TCR-0 chain, potentially allowing immediate surface expression ofan immature TCR-(-CD3 complex as soon as functional rearrangement of a TCR-0 gene locus has been accomplished. Calcium mobilization could be induced by stimulation with anti-CD3e mAb as soon as intracellular TCR-0 was detectable, suggesting that a functional TCR-0-CD3 complex is indeed expressed on the surface of early thymocytes. From day 17 on, most cells were in the DP stage, and over 95% of the DP cells expressed on the TCR-0 chain intracellularly. At day 19 of gestation, extremely low concentrations of TCR-a chain and CD3E were detectable on the cell surface of nearly all thymocytes previously thought to be TCR-CD3 negative. These findings strongly support the hypothesis that maturation to the DP stage depends on surface expression of and subsequent signal transduction through an immature TCR-( .CD3 complex and suggest that maturation to the DP stage by recruitment, if it occurs at all, is of minor relevance. Duringembryogenesis, T lineage committed lymphoidprecursor cells home to the thymus, where they undergo a developmental program, marked by sequential surface expression ofvarious stage specific glycoproteins and rearrangement of the TCR gene loci . One ofthe early thymocyte markers is Pgp-1, a molecule that may play a role in homing of precursor cells to the thymus. Further maturation ofthymocytes results in the expression ofthe ci chain ofthe interleukin-2 receptor (IL-2R) and downregulation of Pgp-1 (for review see 1, 2). The IL-2Ra+ stage coincides with a wave of V > D rearrangements of the TCR-0 locus (3). An important control point in intrathymic development is the subsequent transition into the CD4+8+ stage, accompanied by a burst ofcell divisions, loss ofIL-2Ra expression, and arrest of rearrangement, i.e., allelic exclusion, of the TCR-0 gene locus (4-7). During the DP stage, rearrangement of the TCR-a locus takes place (for review see 8). Upon production of a function...

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supporting

confidence: 91%

Section: Duringembryogenesis T Lineage Committed Lymphoidmentioning

confidence: 99%

Regulation of thymocyte development through CD3. II. Expression of T cell receptor beta CD3 epsilon and maturation to the CD4+8+ stage are highly correlated in individual thymocytes.

Levelt

Carsetti

Eichmann

1993

The Journal of Experimental Medicine

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“…Both quantitative and qualitative differences may exist between the various CD3-ITAMs with respect to their ability to interact with distinct kinases and adaptors (69,70), and the present data predict that CD3␥ contributes primarily in a quantitative manner to TCR signaling. It remains to be investigated whether a TCR lacking the CD3␥-ITAM couples differentially to cytosolic substrates and signaling pathways.…”

Section: Discussionsupporting

confidence: 57%

A Redundant Role of the CD3γ-Immunoreceptor Tyrosine-Based Activation Motif in Mature T Cell Function

Haks¹,

Cordaro²,

Brakel³

et al. 2001

The Journal of Immunology

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At least four different CD3 polypeptide chains are contained within the mature TCR complex, each encompassing one (CD3γ, CD3δ, and CD3ε) or three (CD3ζ) immunoreceptor tyrosine-based activation motifs (ITAMs) within their cytoplasmic domains. Why so many ITAMs are required is unresolved: it has been speculated that the different ITAMs function in signal specification, but they may also serve in signal amplification. Because the CD3ζ chains do not contribute unique signaling functions to the TCR, and because the ITAMs of the CD3-γδε module alone can endow the TCR with normal signaling capacity, it thus becomes important to examine how the CD3γ-, δ-, and ε-ITAMs regulate TCR signaling. We here report on the role of the CD3γ chain and the CD3γ-ITAM in peripheral T cell activation and differentiation to effector function. All T cell responses were reduced or abrogated in T cells derived from CD3γ null-mutant mice, probably because of decreased expression levels of the mature TCR complex lacking CD3γ. Consistent with this explanation, T cell responses proceed undisturbed in the absence of a functional CD3γ-ITAM. Loss of integrity of the CD3γ-ITAM only slightly impaired the regulation of expression of activation markers, suggesting a quantitative contribution of the CD3γ-ITAM in this process. Nevertheless, the induction of an in vivo T cell response in influenza A virus-infected CD3γ-ITAM-deficient mice proceeds normally. Therefore, if ITAMs can function in signal specification, it is likely that either the CD3δ and/or the CD3ε chains endow the TCR with qualitatively unique signaling functions.

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“…A failure of the pre-TCR signaling, as in scid, RAG-1 Ϫ/Ϫ , or RAG-2 Ϫ/Ϫ mice that cannot rearrange TCR genes, results in an arrest at the DN3 stage of development accompanying with apoptosis (3)(4)(5)(6). As expected, introduction of the functional TCR␤-chain into those mice can rescue the transition from DN3 to DP stage and prevent apoptosis (6 -8).…”

mentioning

confidence: 71%

Expression of TCRαβ Partly Rescues Developmental Arrest and Apoptosis of αβ T cells in Bcl11b−/− Mice

Inoue¹,

Kanefuji²,

Okazuka³

et al. 2006

The Journal of Immunology

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Bcl11b −/− mice show developmental arrest at the CD44−CD25+ double-negative 3 (DN3) or immature CD8+single-positive stage of αβ T cell. We have performed detailed analysis of sorted subsets of Bcl11b−/− thymocytes, DN3 and CD44−CD25− double-negative 4 (DN4) cells. Surface expression of TCRβ proteins was not detected in DN3 thymocytes and markedly reduced in DN4 thymocytes, whereas expression within the cell was detected in both, suggesting some impairment in processing of TCRβ proteins from the cytoplasm to the cell surface. This lack of expression, resulting in the absence of pre-TCR signaling, could be responsible for the arrest, but the transgenic TCRβ or TCRαβ expression on the cell surface failed to promote transition from the DN3 to CD4+CD8+ double-positive stage of development. This suggests that the pre-TCR signal cannot compensate the deficiency of Bcl11b for development. Bcl11b−/− DN3 thymocytes showed normal DNA rearrangements between Dβ and Jβ segments but limited DNA rearrangements between Vβ and DJβ without effect of distal or proximal positions. Because this impairment may be due to chromatin accessibility, we have examined histone H3 acetylation in Bcl11b−/− DN3 cells using chromatin immunoprecipitation assay. No change was observed in acetylation at the Vβ and Dβ gene locus. Analysis of Bcl11b−/− DN4 thymocytes showed apoptosis, accompanied with lower expression of anti-apoptotic proteins, Bcl-xL and Bcl-2, than wild-type DN4 thymocytes. Interestingly, the transgenic TCRαβ in those cells reduced apoptosis and raised their protein expression without increased cellularity. These results suggest that Bcl11b deficiency affects many different signaling pathways leading to development arrests.

show abstract

T cell receptor‐negative thymocytes from SCID mice can be induced to enter the CD4/CD8 differentiation pathway

Cited by 73 publications

References 48 publications

Regulation of thymocyte development through CD3. II. Expression of T cell receptor beta CD3 epsilon and maturation to the CD4+8+ stage are highly correlated in individual thymocytes.

Regulation of thymocyte development through CD3. II. Expression of T cell receptor beta CD3 epsilon and maturation to the CD4+8+ stage are highly correlated in individual thymocytes.

A Redundant Role of the CD3γ-Immunoreceptor Tyrosine-Based Activation Motif in Mature T Cell Function

Expression of TCRαβ Partly Rescues Developmental Arrest and Apoptosis of αβ T cells in Bcl11b−/− Mice

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