Immature Recent Thymic Emigrants Are Eliminated by Complement

Hsu, Fan Chi; Shapiro, Michael J.; Chen, Meibo W.; McWilliams, Douglas C.; Seaburg, Lauren; Tangen, Sarah; Shapiro, Virginia Smith

doi:10.4049/jimmunol.1401871

Cited by 21 publications

(59 citation statements)

References 27 publications

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“…RTEs can be distinguished from long-lived MNTs by differential expression of CD45RB and CD55, which are upregulated concurrently with peripheral T cell maturation (27). When naïve splenic T cells were examined, CD55 expression was approximately 10-fold lower in HDAC3-deficient T cells as compared to WT (Figure 1E).…”

Section: Resultsmentioning

confidence: 99%

“…In CD4-cre NKAP cKO mice, the naïve T cell pool was comprised almost entirely of RTEs that are targeted for elimination through the classical complement pathway (16, 27). Therefore, peripheral T cells from CD4-cre HDAC3 cKO mice may also be similarly targeted for destruction through the classical complement pathway.…”

Section: Resultsmentioning

confidence: 99%

“…However, other lectins are highly specific for α2,6-linked sialic acids ( Sambucus nigra back lectin, SNBL) or α2,3-linked sialic acids ( Maacia amurensis lectin, MAL II). While there is not a lectin specific for α2,8-linked sialic acids, recombinant Siglec-E, which preferentially binds to a2,8-linked sialic acids, can be used (27, 33). Previously, we demonstrated that the ligands for Siglec-E are upregulated concomitantly with T cell maturation, and that ligands for Siglec-E are not produced to the same extent in NKAP-deficient T cells as compared to WT (27).…”

Section: Resultsmentioning

confidence: 99%

“…NKAP-deficient RTEs do not die by apoptosis, but rather are eliminated by complement, as demonstrated by C3 deposition on the cell surface. C4 and C1q are also bound to NKAP-deficient T cells, indicating activation of the classical arm of the complement pathway (27). As WT thymocytes mature prior to thymic egress, they increase incorporation of sialic acids into glycoproteins and glycolipids at the cell surface.…”

Section: Introductionmentioning

confidence: 99%

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Histone Deacetylase 3 Is Required for T Cell Maturation

Hsu

Belmonte

Constans

et al. 2015

The Journal of Immunology

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Recent thymic emigrants (RTEs) are newly generated T cells that need to undergo post-thymic maturation to gain functional competency and enter the long-lived naïve T cell pool. The mechanism of T cell maturation remains incompletely understood. Previously, we demonstrated that the transcriptional repressor NKAP is required for T cell maturation. As NKAP associates with histone deacetylase 3 (HDAC3), we examined whether HDAC3 is also required for T cell maturation. While thymic populations are similar in CD4-cre HDAC3 conditional knockout (cKO) mice compared to wild-type (WT) mice, however, the peripheral numbers of CD4+ and CD8+ T cells are dramatically decreased. In the periphery, the majority of HDAC3-deficient naïve T cells are RTEs, indicating a block in T cell maturation. CD55 upregulation during T cell maturation is substantially decreased in HDAC3-deficient T cells. Consistent with a block in functional maturation, HDAC3-deficient peripheral T cells have a defect in TNF licensing after TCR/CD28 stimulation. CD4-cre HDAC3 cKO mice do not have a defect in intrathymic migration, thymic egress, T cell survival or homeostasis. In the periphery, similar to immature NKAP-deficient peripheral T cells, HDAC3-deficient peripheral T cells were bound by IgM and complement proteins, leading to the elimination of these cells. In addition, HDAC3-deficient T cells display decreases in the sialic acid modifications on the cell surface that recruit natural IgM to initiate the classical complement pathway. Therefore, HDAC3 is required for T cell maturation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Histone Deacetylase 3 Is Required for T Cell Maturation

Hsu

Belmonte

Constans

et al. 2015

The Journal of Immunology

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“…The disappearance of naïve NKAP-deficient T cells in the periphery is not due to defective IL-7 signaling, and expression of either Bcl-2 or Bcl-xl transgenes did not restore T cell cellularity in CD4-cre NKAP cKO mice, indicating that apoptosis was unlikely to be responsible (38, 49). Instead, NKAP-deficient T cells are targeted by the classical arm of the complement pathway, and are thus eliminated in the periphery (49). NKAP-deficient RTEs and MNTs exhibit deposition of C3, C4, C1q and IgM on the cell surface.…”

Section: Survival In the Peripherymentioning

confidence: 99%

T Cell Adolescence: Maturation Events Beyond Positive Selection

Hogquist

Xing

Hsu

et al. 2015

The Journal of Immunology

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Single positive (SP) thymocytes that successfully complete positive and negative selection must still undergo one final step, generally termed T cell maturation, before they gain functional competency and enter the long-lived T cell pool. Maturation initiates after positive selection in SP thymocytes, and continues in the periphery in recent thymic emigrants (RTEs), before these newly produced T cells gain functional competency and are ready to participate in the immune response as peripheral naïve T cells. Recent work using genetically altered mice demonstrates that T cell maturation is not a single process, but a series of steps that occur independently and sequentially after positive selection. This review will focus on the changes that occur during T maturation, and the molecules and pathways that are critical at each step.

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Med1 controls thymic T‐cell migration into lymph node through enhancer‐based Foxo1‐Klf2 transcription program

Yuan,

Su,

Gao

et al. 2024

Eur J Immunol

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The migration is the key step for thymic T cells to enter circulation and then lymph nodes (LNs), essential for future immune surveillance. Although promoter‐based transcriptional regulation through Foxo1, Klf2, Ccr7, and Sell regulates T‐cell migration, it remains largely unexplored whether and how enhancers are involved in this process. Here we found that the conditional deletion of Med1, a component of the mediator complex and a mediator between enhancers and RNA polymerase II, caused a reduction of both CD4+ and CD8+ T cells in LNs, as well as a decrease of CD8+ T cells in the spleen. Importantly, Med1 deletion hindered the migration of thymic αβT cells into the circulation and then into LNs, accompanied by the downregulation of KLF2, CCR7, and CD62L. Mechanistically, Med1 promotes Klf2 transcription by facilitating Foxo1 binding to the Klf2 enhancer. Furthermore, forced expression of Klf2 rescued Ccr7 and Sell expression, as well as αβT‐cell migration into LNs. Collectively, our study unveils a crucial role for Med1 in regulating the enhancer‐based Foxo1‐Klf2 transcriptional program and the migration of αβT cells into LNs, providing valuable insights into the molecular mechanisms underlying T‐cell migration.

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Immature Recent Thymic Emigrants Are Eliminated by Complement

Cited by 21 publications

References 27 publications

Histone Deacetylase 3 Is Required for T Cell Maturation

Histone Deacetylase 3 Is Required for T Cell Maturation

T Cell Adolescence: Maturation Events Beyond Positive Selection

Med1 controls thymic T‐cell migration into lymph node through enhancer‐based Foxo1‐Klf2 transcription program

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