bims-indims 2020-09-27 papers

Issue of 2020–09–27
five papers selected by
Harish Narasimhan, Mayo Clinic

Cancer Discov. 2020 Sep 25.

Glucocorticoids Mediate Faulty Tumor-Infiltrating Lymphocyte Function.

Glucocorticoid signaling promoted a dysfunctional phenotype for tumor-infiltrating CD8+ T cells.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2020-140

Int J Mol Sci. 2020 Sep 22. pii: E6966. [Epub ahead of print]21(18):

IL-21 in Homeostasis of Resident Memory and Exhausted CD8 T Cells during Persistent Infection.

CD4 T cells guide the development of CD8 T cells into memory by elaborating mitogenic and differentiation factors and by licensing professional antigen-presenting cells. CD4 T cells also act to stave off CD8 T cell dysfunction during repetitive antigen stimulation in persistent infection and cancer by mitigating generation of exhausted T cells (TEX). CD4 T cell help is also required for establishing and maintaining tissue-resident memory T cells (TRM), the nonrecirculating memory T cell subset parked in nonlymphoid tissues to provide frontline defense against reinvading pathogens. Interleukin (IL)-21 is the signature cytokine secreted by follicular helper CD4 T cells (TFH) to drive B cell expansion and differentiation in germinal centers to mount high-affinity, isotype class-switched antibodies. In several infection models, IL-21 has been identified as the CD4 T help needed for formation and survival of TRM and TEX. In this review, we will explore the different memory subsets of CD8 T cells in persistent infections, the metabolic profiles associated with each, and evidence documenting the importance of CD4 T cell-derived IL-21 in regulating CD8 TRM and TEX development, homeostasis, and function.

Keywords: CD4 T cells; CD8 T cells; exhaustion; interleukin (IL)-21; persistent infection; resident memory

DOI: https://doi.org/10.3390/ijms21186966

Cell. 2020 Sep 04. pii: S0092-8674(20)31154-5. [Epub ahead of print]

COVID-19 Makes B Cells Forget, but T Cells Remember.

Pablo F Cañete, Carola G Vinuesa.

Understanding which arms of the immune response are responsible for protection against SARS-CoV-2 infection is key to predicting long-term immunity and to inform vaccine design. Two studies in this issue of Cell collectively suggest that, although SARS-CoV-2 infection may blunt long-lived antibody responses, immune memory might still be achieved through virus-specific memory T cells.

DOI: https://doi.org/10.1016/j.cell.2020.09.013

Nat Metab. 2020 Sep 21.

Metabolic and epigenetic regulation of T-cell exhaustion.

Fabien Franco, Alison Jaccard, Pedro Romero, Yi-Ru Yu, Ping-Chih Ho.

Current immunotherapies yield remarkable clinical outcomes by boosting the power of host immunity in cancer cell elimination and viral clearance. However, after prolonged antigen exposure, CD8+ T cells differentiate into a special differentiation state known as T-cell exhaustion, which poses one of the major hurdles to antiviral and antitumor immunity during chronic viral infection and tumour development. Growing evidence indicates that exhausted T cells undergo metabolic insufficiency with altered signalling cascades and epigenetic landscapes, which dampen effector immunity and cause poor responsiveness to immune-checkpoint-blockade therapies. How metabolic stress affects T-cell exhaustion remains unclear; therefore, in this Review, we summarize current knowledge of how T-cell exhaustion occurs, and discuss how metabolic insufficiency and prolonged stress responses may affect signalling cascades and epigenetic reprogramming, thus locking T cells into an exhausted state via specialized differentiation programming.

DOI: https://doi.org/10.1038/s42255-020-00280-9

J Clin Invest. 2020 Sep 21. pii: 134091. [Epub ahead of print]

IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis.

Heather J Faust, Hong Zhang, Jin Han, Matthew T Wolf, Ok Hee Jeon, Kaitlyn Sadtler, Alexis N Peña, Liam Chung, David R Maestas, Ada J Tam, Drew M Pardoll, Judith Campisi, Franck Housseau, Daohong Zhou, Clifton O Bingham, Jennifer H Elisseeff.

Senescent cells (SnCs) are implicated in the pathogenesis of age-related diseases including osteoarthritis (OA), in part via expression of a senescence-associated secretory phenotype (SASP) that includes immunologically relevant factors and cytokines. In a model of posttraumatic OA (PTOA), anterior cruciate ligament transection (ACLT) induced a type 17 immune response in the articular compartment and draining inguinal lymph nodes (LNs) that paralleled expression of the senescence marker p16INK4a (Cdkn2a) and p21 (Cdkn1a). Innate lymphoid cells, γδ+ T cells, and CD4+ T cells contributed to IL-17 expression. Intra-articular injection of IL-17-neutralizing antibody reduced joint degeneration and decreased expression of the senescence marker Cdkn1a. Local and systemic senolysis was required to attenuate tissue damage in aged animals and was associated with decreased IL-17 and increased IL-4 expression in the articular joint and draining LNs. In vitro, we found that Th17 cells induced senescence in fibroblasts and that SnCs skewed naive T cells toward Th17 or Th1, depending on the presence of TGF-β. The SASP profile of the inflammation-induced SnCs included altered Wnt signaling, tissue remodeling, and cell-cycle pathways not previously implicated in senescence. These findings provide molecular targets and mechanisms for senescence induction and therapeutic strategies to support tissue healing in an aged environment.

Keywords: Aging; Arthritis; Cellular immune response; Cellular senescence; Immunology

DOI: https://doi.org/10.1172/JCI134091