Inventories of naive and tolerant mouse CD4 T cell repertoires reveal a hierarchy of deleted and diverted T cell receptors.

Deletion or Treg cell differentiation are alternative fates of autoreactive MHCII-restricted thymocytes. How these different modes of tolerance determine the size and composition of polyclonal cohorts of autoreactive T cells with shared specificity is poorly understood. We addressed how tolerance to a naturally expressed autoantigen of the central nervous system shapes the CD4 T cell repertoire. Specific cells in the tolerant peripheral repertoire either were Foxp3+ or displayed anergy hallmarks and, surprisingly, were at least as frequent as in the nontolerant repertoire. Despite this apparent lack of deletional tolerance, repertoire inventories uncovered that some T cell receptors (TCRs) were lost from the CD4 T cell pool, whereas others mediated Treg cell differentiation. The antigen responsiveness of these TCRs supported an affinity model of central tolerance. Importantly, the contribution of different diverter TCRs to the nascent thymic Treg cell population reflected their antigen reactivity rather than their frequency among precursors. This reveals a multilayered TCR hierarchy in CD4 T cell tolerance that separates deleted and diverted TCRs and assures that the Treg cell compartment is filled with cells of maximal permissive antigen reactivity.

[Cefiderocol in AML patient with neutropenic infection due to 4MRGN Klebsiella pneumoniae (VIM-1)]. / Cefiderocol bei AML-Patientin mit neutropenischem Infekt durch 4MRGN Klebsiella pneumoniae (VIM-1).

ANAMNESIS: The 68-year-old patient presented with fever, general malaise and physical weakness in neutropenia during a known relapse of acute myeloid leukaemia after allogeneic stem cell transplantation. TREATMENT/DIAGNOSIS: Due to immune suppression, an empiric antibiotic therapy with piperacillin/tazobactam was started. The 4MRGN screening was positive. For this reason, therapy was switched empirically to ceftazidime/avibactam plus colistin. A tongue ulcer with abscess formation and phlegmonous soft tissue reaction was revealed as the focus of the infection. Several microbiological probes including a blood culture discovered Klebsiella pneumoniae complex - 4MRGN that expressed a metallo-beta-lactamase of the VIM-1 type (Verona integron metallo betalactamase-1). A permanent improvement of the clinical symptoms and regredience of the infection parameters could only be achieved after antibiotic treatment was switched to the recently approved siderophor cephalosporin cefiderocol. After 18 days the antibiotic treatment could be completed successfully. The patient was discharged in a stable condition. CONCLUSION: 4MRGN pathogens are Gram-negative rod-shaped bacteria that are resistant against four main bactericidal antibiotic groups (Acylureidopenicillins, 3rd generation cephalosporins, carbapenems, and fluoroquinolones) and thus difficult to treat. The present case demonstrates good clinical efficacy for cefiderocol even in pathogens resistant to antibiotics such as colistin and ceftazidime/avibactam and highlights the importance of antibiogram-tailored therapy.