Search

This Future Challenges article summarizes views on future directions in immunological research presented at round‐table discussions at the 4th Immunology workshop in the Lofoten Islands in Norway, held in August 2023, and subsequent responses to surveys sent to meeting participants. It also summarizes some of the conversations around the responsibility of scientists to communicate with the non‐science community, and the approaches that we may use to meet this obligation. [ABSTRACT FROM AUTHOR]

Viral mimicry of host cell structures has been postulated to curtail the B cell receptor (BCR) repertoire against persisting viruses through tolerance mechanisms. This concept awaits, however, experimental testing in a setting of natural virus--host relationship. We engineered mouse models expressing a monoclonal BCR specific for the envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV), a naturally persisting mouse pathogen. When the heavy chain of the LCMV-neutralizing antibody KL25 was paired with its unmutated ancestor light chain, most B cells underwent receptor editing, a behavior reminiscent of autoreactive clones. In contrast, monoclonal B cells expressing the same heavy chain in conjunction with the hypermutated KL25 light chain did not undergo receptor editing but exhibited low levels of surface IgM, suggesting that light chain hypermutation had lessened KL25 autoreactivity. Upon viral challenge, these IgMlow cells were not anergic but up-regulated IgM, participated in germinal center reactions, produced antiviral antibodies, and underwent immunoglobulin class switch as well as further affinity maturation. These studies on a persisting virus in its natural host species suggest that central tolerance mechanisms prune the protective antiviral B cell repertoire. [ABSTRACT FROM AUTHOR]

Author(s): Carolyn G King [1]; Takashi Kobayashi [1, 3]; Pedro J Cejas [1]; Taesoo Kim [1]; Kwiyeom Yoon [1, 3]; Gregory K Kim [1]; Elise Chiffoleau [2, 3]; Somia P [...]

Cumulative T-cell receptor signal strength and ensuing T-cell responses are affected by both antigen affinity and antigen dose. Here we examined the distinct contributions of these parameters to CD4 T-cell differentiation during infection. We found that high antigen affinity positively correlates with T helper (Th)1 differentiation at both high and low doses of antigen. In contrast, follicular helper T cell (TFH) effectors are generated after priming with high, intermediate, and low affinity ligand. Unexpectedly, memory T cells generated after priming with very low affinity antigen remain impaired in their ability to generate secondary Th1 effectors, despite being recalled with high affinity antigen. These data challenge the view that only strongly stimulated CD4 T cells are capable of differentiating into the TFH and memory T-cell compartments and reveal that differential strength of stimulation during primary T-cell activation imprints unique and long lasting T-cell differentiation programs. [ABSTRACT FROM AUTHOR]

Summary How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial infections and that these increased acetate concentrations are required for optimal memory CD8 + T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8 + T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH. This context-dependent post-translational modification enhanced GAPDH activity, catalyzing glycolysis and thus boosting rapid memory CD8 + T cell responses. Accordingly, in a murine Listeria monocytogenes model, transfer of acetate-augmented memory CD8 + T cells exerted superior immune control compared to control cells. Our results demonstrate that increased systemic acetate concentrations are functionally integrated by CD8 + T cells and translate into increased glycolytic and functional capacity. The immune system thus directly relates systemic metabolism with immune alertness. [ABSTRACT FROM AUTHOR]

The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active conformation on CD8 + T cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T cells, enhanced effectiveness of bi-specific T cell engaging antibodies, and improved CAR T cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system., Competing Interests: Declaration of interests J. Lötscher and C.H. are inventors on a patent relating to this study filed by the University of Basel (EP20/191392.8), which is being developed by a start-up company (Hornet Therapeutics Ltd—Scientific Founder: C.H.). J.G. is an employee of Hornet Therapeutics. The authors declare no other competing financial interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)