review articles Flashcards
CSR?
Rekha D Jhamnani et.al
Class-Switch Recombination (CSR)/Hyper-IgM (HIGM) Syndromes and Phosphoinositide 3-Kinase (PI3K) Defects
The CSR/HIGM syndromes are defined by the presence of normal or elevated plasma IgM levels in the context of low levels of switched IgG, IgA, and IgE isotypes. Recently described autosomal dominant gain-of-function (GOF) mutations in PIK3CD and PIK3R1 cause combined immunodeficiencies that can also present as CSR/HIGM defects.The CD40L/CD40 engagement in the germinal center, in the presence of the appropriate cytokine milieu, promotes B cells to undergo proliferation, CSR and SHM, through activation of transcription factors, such as nuclear factor-κB (NF-κB). Although in a less effective way, CSR can also be induced in a T-cell-independent manner, via concurrent engagement of BCR or TACI and Toll-like receptors (TLRs) (1–4, 7, 8, 15, 16).
CSR: activation-induced cytidine deaminase (AID) to catalyze the conversion of cytidine nucleotides to uracil. Next, uracil removal by uracil N-glycosylase (UNG), which, along with endonucleases and the mismatch repair (MMR) machinery, facilitates the generation of double-stranded DNA breaks.
SHM?
The SHM process randomly introduces mutations into the Ig V regions, altering the affinity for antigens while maintaining the same Ig C isotype. Uracil residues are introduced by AID and can be further modified by UNG. These transitions and transversions generated at the Ig V region are perpetuated during DNA replication, the MMR process, and error-prone polymerase enzymatic activities.
LINK L14 WITH L16
Great question! The mTOR pathway is more commonly associated with metabolic regulation, cell growth, and differentiation, but recent research highlights its role in class switch recombination (CSR), especially through its influence on B cell metabolism and activation.
mTOR Pathway in CSR
B cell activation requires a shift in metabolic activity, which is heavily regulated by mTOR. Once a B cell is activated by antigens and T cell help (via CD40/CD40L and cytokines like IL-4), it needs to undergo rapid proliferation and metabolic changes to support processes like CSR and somatic hypermutation (SHM).
mTOR’s Role:
Metabolic reprogramming:
mTOR upregulates glycolysis and oxidative phosphorylation, providing the energy and biosynthetic precursors necessary for DNA synthesis and repair during CSR.
Regulation of AID expression:
Activation-induced cytidine deaminase (AID) is crucial for initiating CSR by creating double-strand breaks in switch (S) regions of immunoglobulin genes. mTOR signaling has been shown to influence AID expression indirectly by promoting B cell growth and activation.
Link to cytokines:
Cytokines like IL-4, which drive CSR towards specific isotypes (e.g., IgE and IgG1), can activate the mTOR pathway. This enhances B cell metabolic fitness and ensures proper CSR.
mTOR → HIF-1α → CSR
mTOR activation leads to increased expression of HIF-1α (hypoxia-inducible factor 1-alpha), a transcription factor that promotes glycolysis.
High glycolytic activity is important for rapidly dividing B cells undergoing CSR. Without sufficient metabolic support, B cells fail to complete CSR efficiently.
Akt-mTOR ?
The Akt-mTOR pathway is essential for lymphocyte differentiation, function, and maturation. In T cells, PI3Kδ is mainly activated upon TCR (T-cell receptor), ICOS and IL-2R stimulation. Particularly in CD8+ T cells, the Akt-mTOR pathway is critical for regulating whether naïve cells differentiate into effector or memory cells by controlling the transition from oxidative phosphorylation, a lower energy yielding process, to aerobic glycolysis, better suited for the rapid growth and proliferation needed by effector T cells. Akt also suppresses the transcription factor FOXO1 function via phosphorylation and through PI3Kδ-dependent downregulation of IL-7Rα and CD62L (42, 47, 48).
immunometabolism?
Makowski et.al
Immunometabolism: From basic mechanisms to translation
like effector T cell subsets, regulatory T cells (Tregs) do not require GLUT1 or high levels of glutamine uptake through the amino acid transporter ASCT221,22 and instead predominantly rely on mitochondrial lipid, pyruvate, and lactate oxidation.10,23–25 Tregs can be highly glycolytic, but the primary Treg transcription factor, FoxP3, has also been shown to repress glycolysis and high rates of glucose metabolism can impair Treg suppressive capacity.24,26,27 Individual effector T cell populations also differ, as glutamine metabolism is essential for CD4 Th17 cells, but effector differentiation of CD4 Th1 and CD8 cytotoxic T cells as well as that of classically activated M1-like macrophages is restrained by this pathway.28–30
TCR initiation?
Tewari et.al (2021)
Binding to ITAMs triggers conformational changes that make ZAP-70 more accessible to phosphorylation by Lck and subsequently leads to ZAP-70 autophosphorylation and full activation (3, 4, 5). Activated ZAP-70 is released from ITAMs and proceeds to target its effectors, primarily membrane-bound scaffolding proteins LAT and SLP-76 (6). Phosphorylation of LAT and SLP-76 nucleates the assembly of the multiprotein signaling complex, which further propagates the downstream TCR signaling cascade resulting in activation of the phospholipase PLC-γ1, cytoplasmic calcium release from endoplasmic reticulum, and, ultimately, transcriptional responses associated with T cell activation and clonal expansion (6, 7, 8, 9).
IL-2 importance?
Sinclair LV et al (2013) T-cell receptor and IL-2 signaling leads to increased uptake of large neutral amino acids, including leucine, using System L1 transporters
Zheng Y et al (2009) The impairment of IL-2 production and proliferation is linked to anergic T-cells’ failure to upregulate cellular metabolic machinery.
impaired hif1-a?
Shi LZ et al (2011)
Impaired glycolysis due to HIF1α deficiency prevents Th17 differentiation and favors regulatory T-cells formation.
not review, better description ctla-4 activity?
T-cell activation is a complex process that requires >1 stimulatory signal. TCR binding to MHC provides specificity to T-cell activation, but further costimulatory signals are required. Binding of B7-1 (CD80) or B7-2 (CD86) molecules on the APC with CD28 molecules on the T cell leads to signaling within the T cell. Sufficient levels of CD28:B7-1/2 binding lead to proliferation of T cells, increased T-cell survival, and differentiation through the production of growth cytokines such as interleukin-2 (IL-2), increased energy metabolism, and upregulation of cell survival genes.
CTLA-4 is a CD28 homolog with much higher binding affinity for B77,8; however, unlike CD28, binding of CTLA-4 to B7 does not produce a stimulatory signal. As such, this competitive binding can prevent the costimulatory signal normally provided by CD28:B7 binding7,9,10 (Fig. 1). The relative amount of CD28:B7 binding versus CTLA-4:B7 binding determines whether a T cell will undergo activation or anergy.4 Furthermore, some evidence suggests that CTLA-4 binding to B7 may actually produce inhibitory signals that counteract the stimulatory signals from CD28:B7 and TCR:MHC binding.11,12 Proposed mechanisms for such inhibitory signals include direct inhibition at the TCR immune synapse, inhibition of CD28 or its signaling pathway, or increased mobility of T cells leading to decreased ability to interact with APCs.9,12,13
Stimulatory signals resulting from both TCR and CD28:B7 binding induce upregulation of CTLA-4 on the cell surface by exocytosis of CTLA-4-containing vesicles.14 This process operates in a graded feedback loop whereby stronger TCR signaling elicits more CTLA-4 translocation to the cell surface. In case of a net negative signal through CTLA-4:B7 binding, full activation of T cells is prevented by inhibition of IL-2 production and cell cycle progression.15
L9- CD69 AND tcm?
Gray et.al (2018)
CD69 is thought to act as a retention signal as it inhibits the surface expression of the sphingosine‐1‐phosphate (S1P) receptor 1. S1P is a signalling phospholipid that regulates the migration of immune cells out of lymph nodes into efferent lymphatics, and also guides cells out of tissues towards draining lymph nodes.33, 34, 35 Expression of the integrin CD103 by CD8 Trm cells also contributes to their retention, tethering them to skin or mucosal epithelial cells; it is, however, more rare for CD4 Trm cells to express this molecule.36
tcm: Central memory cells are most likely to be reactivated in secondary lymphoid organs as they lack the chemokine receptors and adhesion molecules necessary to enter peripheral tissues.45 Instead they, like naïve T‐cells, express high levels of CD62L, which enables entry into lymph nodes from the blood via high endothelial venules and CCR7, the chemokine receptor that is also involved in trafficking to and within lymphoid organs.45, 56
While Tcm cells may not rapidly produce protective cytokines, they proliferate upon reactivation, quickly increasing the number of antigen‐specific CD4 T‐cells. These cells can then either remain in the lymphoid organ to help B‐cells or migrate to the site of infection to help tackle the infection directly. As Tcm cells are uncommitted to any particular effector cytokine production, they can differentiate under the influence of the cytokine milieu triggered by the challenge infection.57 Vaccines that drive the generation of Tcm cells may provide less immediate protection than those designed to induce Trm cells; however, they offer an adaptable pool of memory CD4 T‐cells that can protect via multiple pathways.
Tfh?
In primary immune responses, activated CD4 T‐cells drive B‐cell germinal centre reactions leading to the production of high‐affinity class‐switched antibody. The cells that coordinate this response are classed as T follicular helper (Tfh) cells that are initially formed in the T‐cell zone of the lymphoid organ before moving to the developing germinal centre.7 Depending on the type of infection, Tfh cells can produce T helper type 1 or 2 cytokines to drive appropriate antibody class switching.7
how does cd28 stimulation link to metabolic reprogramming?
Proper regulation of lymphocyte function is critical to allow normal immune responses while preventing autoimmunity or immunodeficiency. Lymphocyte metabolism is now appreciated to play a key role in cellular function and homeostasis (1). In T lymphocytes activation through the TCR along with CD28-mediated co-stimulation leads to a rapid increase in expression of the glucose transporter, Glut1, to support increased glucose uptake and metabolism (2, 3). Simultaneously, glutamine oxidation increases and beta-oxidation of fatty acids decreases (4, 5). Overall, glycolysis becomes predominant over oxidative metabolism in activated T cells, leading to a reliance on aerobic glycolysis and glutaminolysis in a metabolic phenotype that resembles that of cancer cells (4, 6). St
2.Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002;16:769–777. doi: 10.1016/s1074-7613(02)00323-0. [DOI] [PubMed] [Google Scholar][Ref list]
