Requirement for CD4 T cell help in generating functional CD8 T cell memory

Although primary CD8 responses to acute infections are independent of CD4 help, it is unknown whether a similar situation applies to secondary responses. We show that depletion of CD4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses by memory CD8 cells to reinfection. Memory CD8 cells generated in CD4+/+ mice responded normally when transferred into CD4-/- hosts, whereas memory CD8 cells generated in CD4-/- mice mounted defective recall responses in CD4+/+ adoptive hosts. These results demonstrate a previously undescribed role for CD4 help in the development of functional CD8 memory.     

Defective CD8 T cell memory following acute infection without CD4 T cell help

The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.     

Activation-driven programmed cell death and T cell receptor zeta eta expression

Activation of spontaneously dividing T cell hybridomas induces interleukin-2 (IL-2) production, a cell cycle block, and programmed cell death. T cell hybridomas that express the T cell antigen receptor (TCR) zeta homodimer (zeta 2), but not the TCR zeta eta heterodimer, were studied. The zeta eta- cells produced little or no inositol phosphates (IP) when stimulated with antigen. In most cases the hydrolysis of phosphoinositides was also impaired after stimulation with antibody to CD3, although one zeta eta- cell produced normal concentrations of IP. The zeta eta- cells slowed their growth and secreted IL-2 in response to both stimuli. However, the zeta eta- cells did not die after activation with antigen. Since activated thymocytes also undergo programmed cell death, these results may have important implications for the role of the zeta eta.TCR in negative selection.     

SLE患者CD4+CD25+调节性T细胞及Foxp3基因表达的研究

目的:研究系统性红斑狼疮(SLE)患者外周血CD 4 CD 25 调节性T细胞及Foxp3基因的表达水平,了解它们在SLE发病机制中的作用。方法:分别收集25例SLE患者(SLE组)及健康人(对照组)外周抗凝静脉血,分离纯化T淋巴细胞。PE标记抗CD 4单抗,F ITC标记的抗CD 25单抗,作双色流式细胞术,分析SLE患者外周血CD 4 CD 25 调节性T细胞百分率,RT-PCR检测T细胞Foxp3 mRNA表达。结果:SLE组外周血CD 4 T、CD 4 CD 25 T细胞百分率及T细胞Foxp3 mRNA水平均低于对照组(P<0.01),并且CD 4 CD 25 T细胞百分率与Foxp3mRNA水平呈依赖关系(P<0.01)。结论:SLE患者外周血存在细胞免疫功能失调,CD 4 CD 25 调节性T细胞数量减少和Foxp3mRNA表达下调可能与SLE的免疫学发病机制有关。     

Structural mutations of the T cell receptor zeta chain and its role in T cell activation

T cell hybridomas that express zeta zeta, but not zeta eta, dimers in their T cell receptors (TCRs) produce interleukin-2 (IL-2) and undergo an inhibition of spontaneous growth when activated by antigen, antibodies to the receptor, or antibodies to Thy-1. Hybridomas without zeta and eta were reconstituted with mutated zeta chains. Cytoplasmic truncations of up to 40% of the zeta molecule reconstituted normal surface assembly of TCRs, but antigen-induced IL-2 secretion and growth inhibition were lost. In contrast, cross-linking antibodies to the TCR activated these cells. A point mutation conferred the same signaling phenotype as did the truncations and caused defective antigen-induced tyrosine kinase activation. Thus zeta allows the binding of antigen/major histocompatibility complex (MHC) to alpha beta to effect TCR signaling.     

Inhibition of T cell receptor expression and function in immature CD4+CD8+ cells by CD4

Most immature CD4+CD8+ thymocytes express only a small number of T cell receptor (TCR) molecules on their surface, and the TCR molecules they do express are only marginally capable of transducing intracellular signals. TCR expression and function was not intrinsically low in immature CD4+CD8+ thymocytes, but was found to be actively inhibited by CD4-mediated signals. Indeed, release of CD4+CD8+ thymocytes from CD4-mediated signals resulted in significant increases in both TCR expression and signaling function. These results suggest that, in CD4+CD8+ cells developing in the thymus, increased TCR expression and function requires release from CD4-mediated inhibition.     

A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8

The T cell coreceptors CD4 and CD8 both associate via their cytoplasmic tails with the N-terminus of the Src-family tyrosine kinase Lck. These interactions require zinc and are critical for T cell development and activation. We examined the folding and solution structures of ternary CD4-Lck-Zn2+ and CD8alpha-Lck-Zn2+ complexes. The coreceptor tails and the Lck N-terminus are unstructured in isolation but assemble in the presence of zinc to form compactly folded heterodimeric domains. The cofolded complexes have similar "zinc clasp" cores that are augmented by distinct structural elements. A dileucine motif required for clathrin-mediated endocytosis of CD4 is masked by Lck.     

Distinct pathways of antigen uptake and intracellular routing in CD4 and CD8 T cell activation

The mechanisms that allow antigen-presenting cells (APCs) to selectively present extracellular antigen to CD8+ effector T cells (cross-presentation) or to CD4+ T helper cells are not fully resolved. We demonstrated that APCs use distinct endocytosis mechanisms to simultaneously introduce soluble antigen into separate intracellular compartments, which were dedicated to presentation to CD8+ or CD4+ T cells. Specifically, the mannose receptor supplied an early endosomal compartment distinct from lysosomes, which was committed to cross-presentation. These findings imply that antigen does not require intracellular diversion to access the cross-presentation pathway, because it can enter the pathway already during endocytosis.     

Naive and memory CD4+ T cell survival controlled by clonal abundance

Immunity to a plethora of microbes depends on a diverse repertoire of na?ve lymphocytes and the production of long-lived memory cells. We present evidence here that low clonal abundance in a polyclonal repertoire favors the survival and activation of na?ve CD4(+) T cells as well as the survival of their memory cell progeny. The inverse relation between clonal frequency and survival suggests that intraclonal competition could help maintain an optimally diverse repertoire of T cells and an optimal environment for the generation of long-lived memory cells.     

Molecular cloning of the zeta chain of the T cell antigen receptor

The T cell antigen receptor is a multi-subunit receptor complex present on the surface of all mature and many developing T cells. It consists of clonotypic heterodimers noncovalently linked to five invariant chains that are encoded by four genes and referred to as the CD3 complex. The CD3 gamma, delta, and epsilon chains have been molecularly characterized. In this report the molecular cloning of a complementary DNA encoding the zeta chain of the murine T cell antigen receptor is described. The predicted protein sequence of the zeta chain suggests a structure distinct from those of any of the previously described receptor subunits.     

Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function

CD4+ regulatory T (Treg) cells have a profound ability to suppress host immune responses, yet little is understood about how these cells are regulated. We describe a mechanism linking Toll-like receptor (TLR) 8 signaling to the control of Treg cell function, in which synthetic and natural ligands for human TLR8 can reverse Treg cell function. This effect was independent of dendritic cells but required functional TLR8-MyD88-IRAK4 signaling in Treg cells. Adoptive transfer of TLR8 ligand-stimulated Treg cells into tumor-bearing mice enhanced anti-tumor immunity. These results suggest that TLR8 signaling could play a critical role in controlling immune responses to cancer and other diseases.     

T cell CD3-zeta eta heterodimer expression and coupling to phosphoinositide hydrolysis

The T cell antigen receptor consists of an antigen-binding heterodimer that is noncovalently associated with at least five CD3 subunits (gamma, delta, epsilon, zeta, and eta). The CD3-zeta chains are either disulfide-linked homodimers (CD3-zeta 2) or disulfide-linked heterodimers with eta (CD3-zeta eta). Variants of a murine antigen-specific T cell hybridoma that express normal amounts of CD3-zeta 2 but decreased amounts of CD3-zeta eta were isolated. When activated, the parental cell line increased both phosphatidylinositol hydrolysis and serine-specific protein kinase activity to a much greater extent than the variants. In contrast, the activation of a tyrosine-specific kinase after stimulation with a cross-linking antibody to CD3 was similar among these cells. There was a positive linear relation between the expression of CD3-zeta eta and phosphoinositide hydrolysis stimulated by the TCR, suggesting a differential coupling of the T cell alpha beta heterodimer to signal transduction mechanisms due to alpha beta association with either CD3-zeta 2 or CD3-zeta eta.     

Antigen recognition determinants of gammadelta T cell receptors

The molecular basis of gammadelta T cell receptor (TCR) recognition is poorly understood. Here, we analyze the TCR sequences of a natural gammadelta T cell population specific for the major histocompatibility complex class Ib molecule T22. We find that T22 recognition correlates strongly with a somatically recombined TCRdelta complementarity-determining region 3 (CDR3) motif derived from germ line-encoded residues. Sequence diversity around these residues modulates TCR ligand-binding affinities, whereas V gene usage correlates mainly with tissue origin. These results show how an antigen-specific gammadelta TCR repertoire can be generated at a high frequency and suggest that gammadelta T cells recognize a limited number of antigens.     

CD8alphaalpha-mediated survival and differentiation of CD8 memory T cell precursors

Memory T cells are long-lived antigen-experienced T cells that are generally accepted to be direct descendants of proliferating primary effector cells. However, the factors that permit selective survival of these T cells are not well established. We show that homodimeric alpha chains of the CD8 molecule (CD8alphaalpha) are transiently induced on a selected subset of CD8alphabeta+ T cells upon antigenic stimulation. These CD8alphaalpha molecules promote the survival and differentiation of activated lymphocytes into memory CD8 T cells. Thus, memory precursors can be identified among primary effector cells and are selected for survival and differentiation by CD8alphaalpha.     

CTLA-4 control over Foxp3+ regulatory T cell function

Naturally occurring Foxp3+CD4+ regulatory T cells (Tregs) are essential for maintaining immunological self-tolerance and immune homeostasis. Here, we show that a specific deficiency of cytotoxic T lymphocyte antigen 4 (CTLA-4) in Tregs results in spontaneous development of systemic lymphoproliferation, fatal T cell-mediated autoimmune disease, and hyperproduction of immunoglobulin E in mice, and it also produces potent tumor immunity. Treg-specific CTLA-4 deficiency impairs in vivo and in vitro suppressive function of Tregs-in particular, Treg-mediated down-regulation of CD80 and CD86 expression on dendritic cells. Thus, natural Tregs may critically require CTLA-4 to suppress immune responses by affecting the potency of antigen-presenting cells to activate other T cells.     

Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone

Nonobese diabetic (NOD) mice develop an autoimmune form of diabetes, becoming hyperglycemic after 3 months of age. This process was accelerated by injecting young NOD mice with CD4+ islet-specific T cell clones derived from NOD mice. Overt diabetes developed in 10 of 19 experimental animals by 7 weeks of age, with the remaining mice showing marked signs of the disease in progress. Control mice did not become diabetic and had no significant pancreatic infiltration. This work demonstrates that a CD4 T cell clone is sufficient to initiate the disease process in the diabetes-prone NOD mouse.     

CD4^＋T细胞表位预测及其应用

目前,运用生物软件预测CD4^＋T细胞表位的技术越来越成熟,为表位疫苗的研究提供了有利的条件。对T细胞表位预测技术及其应用进行了综述。     

Demethylated CD8 gene in CD4+ T cells suggests that CD4+ cells develop from CD8+ precursors

Mature T cells and medullary thymocytes bear either the CD4 or CD8 differentiation antigen. Precursor cells in the thymus express neither CD4 nor CD8 (CD4-8-), but most cortical thymocytes are CD4+8+. Whether CD4+ and CD8+ mature T cells arise directly from CD4-8- precursors or from a CD4+8+ intermediate remains unresolved. In this study, methylation of the CD8 gene in murine T cells and thymocytes was examined. There was progressive demethylation of the CD8 gene in the thymus during the transition from CD4-8- to CD4+8+. A similar pattern of demethylation of the CD8 gene was seen in CD4+ mature T cells, suggesting previous expression of CD8 in the CD4+ lineage.     

A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory

The delivery of CD4 help to CD8+ T cell responses requires interactions between CD40 and CD40 ligand and is thought to occur through antigen-presenting cell (APC) activation. Here we show that generation of memory CD8+ T cells displaying an enhanced capacity for cell division and cytokine secretion required CD4 help but not CD40 expression by the APCs. Activated CD4+ and CD8+ T cells expressed CD40; and in the absence of this protein, CD8+ T cells were unable to differentiate into memory cells or receive CD4 help. These results suggest that, like B cells, CD8+ T cells receive CD4 help directly through CD40 and that this interaction is fundamental for CD8+ T cell memory generation.