On Our Way to a Better Understanding of CD8 T Cell Differentiation and Memory T Cell Development.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-52-sci-52 ◽  
Author(s):  
Susan Kaech
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bacterial Infections ◽  
T Cell Development ◽  
Cell Types ◽  
Cell Potential ◽  
Effector Cells ◽  
Memory T Cell ◽  
Different Types ◽  
Two Populations

Abstract As certain acute viral or bacterial infections resolve, two types of effector CD8 T cells are formed that differ in their longevity and memory T-cell potential. These cell types can be distinguished from one another by surface markers, namely IL-7R and KLRG1. Memory precursor effector cells are enriched in the IL-7Rhi KLRG1lo cell population, and short-lived effector cells are enriched in the KLRGhi IL-7Rlo population. These two populations become discernible during the peak of clonal expansion. Upon expression of KLRG1, the effector cells are committed to becoming short-lived. Our recent progress toward identifying the signals and genetic pathways that control the formation of these different types of effector T cells will be discussed.

scholarly journals Requirement of dendritic cells and B cells in the clonal deletion of Mls-reactive T cells in the thymus.

1991 ◽  
Vol 173 (3) ◽  
pp. 539-547 ◽  
Author(s):  
O Mazda ◽  
Y Watanabe ◽  
J Gyotoku ◽  
Y Katsura
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Clonal Deletion ◽  
Fetal Thymus ◽  
Effector Cells

The present study was performed to identify cells responsible for the elimination of T cells reactive with minor lymphocyte-stimulating (Mls) antigens during T cell development. Experiments were carried out in a fetal thymus organ culture (FTOC) system. To examine the tolerance-inducing activity, various populations of cells from adult CBA/J (Mls-1a) mice were injected into deoxyguanosine (dGuo)-treated FTOC of C3H/He (Mls-1b) mice with a microinjector, and 2 d later, the thymus lobes were injected with fetal thymus cells from C3H/He mice as T cell precursors. After 14 d of cultivation, cells were harvested and assayed for the expression of the T cell receptor V beta 6 element. The absence or marked reduction of T cells expressing V beta 6 at high levels (V beta 6high) was regarded as indicating the deletion of Mls-1a-reactive T cells. T cell-depleted populations of thymic as well as splenic cells from CBA/J mice were able to induce clonal deletion. Further characterization of the effector cells was carried out by fractionating the spleen cells before injecting them into dGuo-FTOC. None of the dish-adherent population, dish-nonadherent population, or purified B cells alone were able to induce clonal deletion, whereas the addition of purified B cells to adherent cells restored tolerance inducibility. It was further shown that a combination of CBA/J B cells and C3H/He dendritic cells was effective in eliminating Mls-reactive clones. These results indicate that for the deletion of clones reactive with Mls antigens during T cell development in the thymus, both DC and B cells are required.

scholarly journals Deletion of the mitochondria-shaping protein Opa1 during early thymocyte maturation impacts mature memory T cell metabolism

2021 ◽  
Author(s):  
Mauro Corrado ◽  
Dijana Samardžić ◽  
Marta Giacomello ◽  
Nisha Rana ◽  
Erika L. Pearce ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Effector Memory ◽  
Long Term Memory ◽  
Memory T Cell ◽  
T Cell Function

AbstractOptic atrophy 1 (OPA1), a mitochondria-shaping protein controlling cristae biogenesis and respiration, is required for memory T cell function, but whether it affects intrathymic T cell development is unknown. Here we show that OPA1 is necessary for thymocyte maturation at the double negative (DN)3 stage when rearrangement of the T cell receptor β (Tcrβ) locus occurs. By profiling mitochondrial function at different stages of thymocyte maturation, we find that DN3 cells rely on oxidative phosphorylation. Consistently, Opa1 deletion during early T cell development impairs respiration of DN3 cells and reduces their number. Opa1-deficient DN3 cells indeed display stronger TCR signaling and are more prone to cell death. The surviving Opa1−/− thymocytes that reach the periphery as mature T cells display an effector memory phenotype even in the absence of antigenic stimulation but are unable to generate metabolically fit long-term memory T cells. Thus, mitochondrial defects early during T cell development affect mature T cell function.

Changes in the lymph node microenvironment induced by oncostatin M

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1397-1404 ◽  
Author(s):  
Isabelle Louis ◽  
Gaël Dulude ◽  
Sophie Corneau ◽  
Sylvie Brochu ◽  
Catherine Boileau ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Development ◽  
Cell Development ◽  
Oncostatin M ◽  
Memory Phenotype ◽  
Memory T Cell ◽  
Cell Pool

Abstract Oncostatin M (OM) transforms the lymph node (LN) into a “super lymphoid organ” with 2 striking features: massive thymus-independent T-cell development and major expansion of the memory T-cell pool. We report that T-cell development in the LckOM LN is regulated by a cyclooxygenase-2 (COX-2)–dependent neoangiogenesis involving high endothelial venules (HEVs). That LN HEVs are particularlyrich in OM-receptor β-chain provides aplausible explanation for the fact that extrathymic T-cell development in LckOM mice is limited to the LN. Moreover, we found that increased production of the CCL20 chemokine by LN stromal cells was instrumental in the expansion of the memory phenotype CD4 T-cell pool in LckOM mice. The generality of the latter finding was demonstrated by the fact that CCL20/CCR6 interactions increase the basal proliferation rate of CD62Llo CD4 T cells irrespective of their thymic (in non–OM-transgenic mice) or extrathymic (in LckOM mice) origin. To our knowledge, CCL20 is the first molecule found to increase the proliferation of memory phenotype CD4 T cells. These findings identify potential targets for the creation of thymic substitutes (LN HEVs) and for expansion of the CD4 memory T-cell compartment (CCL20).

scholarly journals B cell adaptor for PI3-kinase (BCAP) modulates CD8+ effector and memory T cell differentiation

2018 ◽  
Vol 215 (9) ◽  
pp. 2429-2443 ◽  
Author(s):  
Mark D. Singh ◽  
Minjian Ni ◽  
Jenna M. Sullivan ◽  
Jessica A. Hamerman ◽  
Daniel J. Campbell
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
B Cell ◽  
Cd8 T Cells ◽  
T Cell Development ◽  
Cell Development ◽  
T Cell Differentiation ◽  
Pi3k Signaling ◽  
Memory T Cell

CD8+ T cells respond to signals via the T cell receptor (TCR), costimulatory molecules, and immunoregulatory cytokines by developing into diverse populations of effector and memory cells. The relative strength of phosphoinositide 3-kinase (PI3K) signaling early in the T cell response can dramatically influence downstream effector and memory T cell differentiation. We show that initial PI3K signaling during T cell activation results in up-regulation of the signaling scaffold B cell adaptor for PI3K (BCAP), which further potentiates PI3K signaling and promotes the accumulation of CD8+ T cells with a terminally differentiated effector phenotype. Accordingly, BCAP-deficient CD8+ T cells have attenuated clonal expansion and altered effector and memory T cell development following infection with Listeria monocytogenes. Thus, induction of BCAP serves as a positive feedback circuit to enhance PI3K signaling in activated CD8+ T cells, thereby acting as a molecular checkpoint regulating effector and memory T cell development.

scholarly journals H-2 antigens of the thymus determinelymphocyte specificity

1978 ◽  
Vol 148 (3) ◽  
pp. 766-775 ◽  
Author(s):  
PJ Fink ◽  
MJ Bevan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Activity ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
Effector Cells ◽  
Minor Histocompatibility Antigens ◽  
Lymph Node Cells ◽  
Two Populations ◽  
Better Than

After immunization, normal H-2 heterozygous mice (for example H-2(b) × H-2(d)) generate two populations of cytotoxic effector T cells, one specific for target cells expressing H-2(b)-plus-antigen and the other specific for H- 2(d)-plus-antigen. With a multideterminant antigen, these two populations have about the same activity. We show here that the H-2 type of resident cells in the thymus determines the H-2 preference of cytotoxic T lymphocytes. F(1)(B 10 × B 10.D2) (H-2(b) × H-2 (d)) mice were thymectomized, lethally irradiated, and reconstituted with T-cell-depleted syngeneic hematopoietic cells. Groups of such ATXBM mice were grafted subcutaneously with neonatal thymus lobes from parental mice, either B10 (H-2 (b)) or B10.D2 (H-2(d)). 2-3 mo later, the mice were immunized against the minor histocompatibility antigens on F(1)(BALB/c × BALB.B) cells and assayed for cytotoxic T-cell activity. H-2(b) × H-2(d) ATXBM mice with H-2(b) thymus grafts responded to antigen-plus-H-2(b) much better than to antigen-plus-H-2(d), and vice versa for the mice with H-2(d) thymus grafts. As judged by antiserum treatment, the effector cells were of F(1) origin. To explore the possibility that the "thymus preference" may have been due to suppression of T-cell activity, nonimmune spleen and lymph node cells from normal H-2(b) × H-2(d) mice and cells from H-2(b) × H-2(d) mice bearing a homozygous thymus were mixed 1:1 and immunized in adoptive transfer. The mixture responded to antigen-plus-H-2(b) and antigen-plus-H-2(d) equally well, demonstrating that the cells that showed a "thymus preference" could not suppress a response to antigen in association with the nonthymic H-2 type. We conclude from these and other experiments that H-2 antigens present on resident cells of the thymus determine the spectrum of specificity of T cells which mature in that thymus and eventually make up the peripheral T- cell pool.

scholarly journals Self-reactive and transplacental-acquired maternal T cells in SCID patients—time to update

2015 ◽  
Vol 2 (1) ◽  
pp. 47-52
Author(s):  
Raz Somech
Keyword(s):  
T Cells ◽  
T Cell ◽  
Unusual Case ◽  
Cell Function ◽  
Functional Characterization ◽  
Severe Combined Immunodeficiency ◽  
T Cell Development ◽  
Cell Types ◽  
T Cell Differentiation

Patients with severe combined immunodeficiency (SCID) typically present with profoundly reduced T cells. In some cases, however, T cells may be affected by defects that allow some T-cell development but compromise T-cell function such as in Omenn syndrome (OS), which is characterized by impaired T cell differentiation in the presence of abnormal self-reactive cells. One distinctive feature of SCID patients, which can sometimes resemble the clinical picture of OS, is the presence of alloreactive cells that originated from transplacentally acquired maternal T lymphocytes. The traditional view is that self-reactive cells and transplacentally acquired maternal T cells cannot occur concomitantly in the same OS patient. This review provides an updated functional characterization of transplacentally acquired maternal T cells and compares them with the T cells of an OS patient. An unusual case of an immunodeficient SCID patient with a mild OS phenotype is also presented. This patient had both self-reactive cells and transplacentally acquired maternal T cells, allowing us to simultaneously evaluate the function and tolerance capacities of both cell types. We propose that coexistence of autologous and maternal T cells in patients exhibiting mild OS symptoms was rejected because it had not been studied before and not because the cells are mutually exclusive. Moreover, taking into consideration the milder clinical phenotype associated with transplacentally acquired maternal T cells in SCID patients, we believe that these cells may provide some degree of immunity and prevent autoimmunity, even though they do not actually function to protect against infections. Statement of novelty: Autologous and transplacental-acquired maternal T cells can coexist in the same SCID patient. Although both cell types are nonfunctional for protecting against infections, maternal cells provide some degree of immunity and therefore are associated with only mild GVHD symptoms.

scholarly journals Recent thymic emigrants are tolerized in the absence of inflammation

2016 ◽  
Vol 213 (6) ◽  
pp. 913-920 ◽  
Author(s):  
Travis J. Friesen ◽  
Qingyong Ji ◽  
Pamela J. Fink
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cell ◽  
Cytokine Production ◽  
T Cell Development ◽  
Tolerance Induction ◽  
Recent Thymic Emigrants ◽  
Effector Cells ◽  
Elevated Expression

T cell development requires a period of postthymic maturation. Why this is the case has remained a mystery, particularly given the rigors of intrathymic developmental checkpoints, successfully traversed by only ∼5% of thymocytes. We now show that the first few weeks of T cell residence in the lymphoid periphery define a period of heightened susceptibility to tolerance induction to tissue-restricted antigens (TRAs), the outcome of which depends on the context in which recent thymic emigrants (RTEs) encounter antigen. After encounter with TRAs in the absence of inflammation, RTEs exhibited defects in proliferation, diminished cytokine production, elevated expression of anergy-associated genes, and diminished diabetogenicity. These properties were mirrored in vitro by enhanced RTE susceptibility to regulatory T cell–mediated suppression. In the presence of inflammation, RTEs and mature T cells were, in contrast, equally capable of inducing diabetes, proliferating, and producing cytokines. Thus, recirculating RTEs encounter TRAs during a transitional developmental stage that facilitates tolerance induction, but inflammation converts antigen-exposed, tolerance-prone RTEs into competent effector cells.

scholarly journals Distinct features of dendritic cells and anti-Ig activated B cells as stimulators of the primary mixed leukocyte reaction.

1989 ◽  
Vol 169 (1) ◽  
pp. 239-254 ◽  
Author(s):  
J P Metlay ◽  
E Puré ◽  
R M Steinman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Types ◽  
Cell Clustering ◽  
Class Ii Mhc ◽  
Distinct Features ◽  
Relative Potencies ◽  
Two Populations ◽  
Strain Dependent

Highly enriched populations of B lymphoblasts have been isolated after culture with anti-Ig-Sepharose and compared with dendritic cells as stimulators of CD4+ T cells in the murine MLR. The two populations clearly differed in phenotype; anti-Ig blasts were FcR+, B220+, 33D1-, while dendritic cells were FcR-, B220-, 33D1+. However, as MLR stimulators, they shared many common features. Both cells (a) expressed comparable levels of class II MHC products; (b) independently stimulated the primary MLR and the production of several T derived lymphokines including IL-2 and IL-4; and (c) were comparable in stimulating freshly sensitized T cells. However, the relative potencies of dendritic cells and anti-Ig blasts as primary MLR stimulators varied in a strain-dependent fashion. Only anti-Ig blasts could stimulate across an Mls barrier, being at least 100 times more active in stimulating Mls-mismatched, MHC-matched T cells, relative to syngeneic T cells. In contrast, dendritic cells were 10-30 times more potent than anti-Ig blasts when stimulating across an MHC barrier and were likewise more effective in binding MHC-disparate T cells to form the clusters in which the MLR was generated. Dendritic cell-T cell clustering was resistant to anti-LFA-1 mAb, while B blast-T cell clustering was totally blocked. Thus, anti-Ig B lymphoblasts and dendritic cells, two cell types which differ markedly in phenotype, also differ in efficiency and mechanism for initiating responses in allogeneic T cells.

scholarly journals Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Cheng-Tao Jiang ◽  
Kai-Ge Chen ◽  
An Liu ◽  
Hua Huang ◽  
Ya-Nan Fan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Noncovalent Interactions ◽  
Killer Cell ◽  
Antibody Immobilization ◽  
Effector Cells ◽  
Nanoparticle Surface

AbstractModulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an ‘adaptor’ while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.

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