BATF3 programs CD8 T cell memory.

Antiviral CD8 T cell responses are characterized by an initial activation/priming of T lymphocytes followed by a massive proliferation, subset differentiation, population contraction and the development of a stable memory pool. The transcription factor BATF3 has been shown to play a central role in the development of conventional dendritic cells, which in turn are critical for optimal priming of CD8 T cells. Here we show that BATF3 was expressed transiently within the first days after T cell priming and had long-lasting T cell-intrinsic effects.

On-target restoration of a split T cell-engaging antibody for precision immunotherapy.

T cell-engaging immunotherapies are changing the landscape of current cancer care. However, suitable target antigens are scarce, restricting these strategies to very few tumor types. Here, we report on a T cell-engaging antibody derivative that comes in two complementary halves and addresses antigen combinations instead of single molecules.

SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7 normal lymphocytes.

SLAMF7 is under intense investigation as a target for immunotherapy in multiple myeloma. In this study, we redirected the specificity of T cells to SLAMF7 through expression of a chimeric antigen receptor (CAR) derived from the huLuc63 antibody (elotuzumab) and demonstrate that SLAMF7-CAR T cells prepared from patients and healthy donors confer potent antimyeloma reactivity. We confirmed uniform, high-level expression of SLAMF7 on malignant plasma cells in previously untreated and in relapsed/refractory (R/R) myeloma patients who had received previous treatment with proteasome inhibitors and immunomodulatory drugs.

Minicircle-Based Engineering of Chimeric Antigen Receptor (CAR) T Cells.

Plasmid DNA is being used as a pharmaceutical agent in vaccination, as well as a basic substance and starting material in gene and cell therapy, and viral vector production. Since the uncontrolled expression of backbone sequences present in such plasmids and the dissemination of antibiotic resistance genes may have profound detrimental effects, an important goal in vector development was to produce supercoiled DNA lacking bacterial backbone sequences: Minicircle (MC) DNA. The Sleeping Beauty (SB) transposon system is a non-viral gene delivery platform enabling a close-to-random profile of genomic integration.

Interrupting CD28 costimulation before antigen rechallenge affects CD8(+) T-cell expansion and effector functions during secondary response in mice.

The role of CD28-mediated costimulation in secondary CD8(+) T-cell responses remains controversial. Here, we have used two tools - blocking mouse anti-mouse CD28-specific antibodies and inducible CD28-deleting mice - to obtain definitive answers in mice infected with ovalbumin-secreting Listeria monocytogenes. We report that both blockade and global deletion of CD28 reveal its requirement for full clonal expansion and effector functions such as degranulation and IFN-γ production during the secondary immune response.

Sequential induction of effector function, tissue migration and cell death during polyclonal activation of mouse regulatory T-cells.

The ability of CD4(+)Foxp3(+) regulatory T-cells (Treg) to produce interleukin (IL)-10 is important for the limitation of inflammation at environmental interfaces like colon or lung. Under steady state conditions, however, few Tregs produce IL-10 ex vivo. To investigate the origin and fate of IL-10 producing Tregs we used a superagonistic mouse anti-mouse CD28 mAb (CD28SA) for polyclonal in vivo stimulation of Tregs, which not only led to their numeric expansion but also to a dramatic increase in IL-10 production.

Interruption of CD28-mediated costimulation during allergen challenge protects mice from allergic airway disease.

Background: Allergic asthma is a T(H)2-promoted hyperreactivity with an immediate, IgE, and mast cell-dependent response followed by eosinophil-dominated inflammation and airway obstruction.

Objective: Because costimulation by CD28 is essential for T(H)2 but not T(H)1 responses, we investigated the effect of selective interference with this pathway in mice using the models of ovalbumin and house dust mite-induced airway inflammation.

Methods: To study the role of CD28 in the effector phase of allergic airway inflammation, we developed an inducibly CD28-deleting mouse strain or alternatively used a CD28 ligand-binding site-specific mouse anti-mouse mAb blocking CD28 engagement.

Cell-intrinsic and -extrinsic control of Treg-cell homeostasis and function revealed by induced CD28 deletion.

While the requirement for CD28 and its ligands for the generation and function of "natural" (n)Treg cells is well established, it has not been possible yet to investigate cell-intrinsic effects after interrupted CD28 expression. Here, we demonstrate a selective loss of Treg cells after disruption of the CD28 gene. The decline in Treg-cell number was accompanied by reduced homeostatic proliferation, probably due to lack of costimulation during self-antigen recognition, and by impaired Treg-cell function including downregulation of CTLA-4.

Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1).

Inducible cAMP early repressor (ICER) is a transcriptional repressor, which, because of alternate promoter use, is generated from the 3' region of the cAMP response modulator (Crem) gene. Its expression and nuclear occurrence are elevated by high cAMP levels in naturally occurring regulatory T cells (nTregs). Using two mouse models, we demonstrate that nTregs control the cellular localization of ICER/CREM, and thereby inhibit IL-2 synthesis in conventional CD4(+) T cells.

CD28 and IL-4: two heavyweights controlling the balance between immunity and inflammation.

The costimulatory receptor CD28 and IL-4Ralpha containing cytokine receptors play key roles in controlling the size and quality of pathogen-specific immune responses. Thus, CD28-mediated costimulation is needed for effective primary T-cell expansion and for the generation and activation of regulatory T-cells (Treg cells), which protect from immunopathology. Similarly, IL-4Ralpha signals are required for alternative activation of macrophages, which counteract inflammation by type 1 responses.

Rapid regulatory T-cell response prevents cytokine storm in CD28 superagonist treated mice.

Superagonistic CD28-specific monoclonal antibodies (CD28SA) are highly effective activators of regulatory T-cells (Treg cells) in rats, but a first-in-man trial of the human CD28SA TGN1412 resulted in an unexpected cytokine release syndrome. Using a novel mouse anti-mouse CD28SA, we re-investigate the relationship between Treg activation and systemic cytokine release. Treg activation by CD28SA was highly efficient but depended on paracrine IL-2 from CD28SA-stimulated conventional T-cells.

Proliferative signals mediated by CD28 superagonists require the exchange factor Vav1 but not phosphoinositide 3-kinase in primary peripheral T cells.

Almost all responses of naive T cells require co-stimulation, i.e. engagement of the clonotypic TCR with relevant antigen/MHC and the co-stimulatory molecule CD28.

Inhibition of IL-4/IL-13 does not enhance the efficacy of allergen immunotherapy in murine allergic airway inflammation.

Background: Successful allergen-specific immunotherapy (SIT) is associated with reduced Th2 cytokine production and the induction of IL-10-producing regulatory T cells. To improve treatment efficacy, we investigated the impact of an IL-4/IL-13 inhibitor during SIT.

Methods: BALB/c mice were sensitized intranasally with ovalbumin (OVA) for 4 weeks.