Pleiotropic effects of antibiotics on T cell metabolism and T cell-mediated immunity

Abstract

T cells orchestrate adaptive and innate immune responses against pathogens and transformed cells. However, T cells are also the main adaptive effector cells that mediate allergic and autoimmune reactions. Within the last few years, it has become abundantly clear that activation, differentiation, effector function, and environmental adaptation of T cells is closely linked to their energy metabolism. Beyond the provision of energy equivalents, metabolic pathways in T cells generate building blocks required for clonal expansion. Furthermore, metabolic intermediates directly serve as a source for epigenetic gene regulation by histone and DNA modification mechanisms. To date, several antibiotics were demonstrated to modulate the metabolism of T cells especially by altering mitochondrial function. Here, we set out to systematically review current evidence about how beta-lactam antibiotics, macrolides, fluoroquinolones, tetracyclines, oxazolidinones, nitroimidazoles, and amphenicols alter the metabolism and effector functions of CD4+ T helper cell populations and CD8+ T cells in vitro and in vivo. Based on this evidence, we have developed an overview on how the use of these antibiotics may be beneficial or detrimental in T cell-mediated physiological and pathogenic immune responses, such as allergic and autoimmune diseases, by altering the metabolism of different T cell populations.

Structural Basis of T Cell Toxicity Induced by Tigecycline Binding to the Mitochondrial Ribosome

“…Given our observations in cell lines (Fig. S1B) and previous research indicating differential susceptibility to antibiotics by specialized T cell subsets 12,13 , we FACS-isolated naïve (CD45RA + CD27 + ) and memory (CD45RA -CD27 + ) CD4 + T cells and compared proliferation in the presence or absence of tigecycline (Fig. 1I-J).…”

“…We rst compared the survival of immortalized Jurkat T cells and HeLa cells in the presence of chloramphenicol or doxycycline, two important bacterial ribosome-targeting antibiotics associated with white blood cell phenotypes 13,[15][16][17][18][19][20][21] . We found chloramphenicol to reduce the survival of both cell lines after 3 and 5 days of treatment (Jurkat IC50 = 25.85 µM; HeLa IC50 = 41.71 µM, after 5 days).…”

“…Naive lymphocytes fundamentally depend upon OXPHOS to power clonal expansion [6][7][8][9] , something which if inhibited can affect the effector-memory response [6][7][8][9] . On the other hand, such inhibition could explain the bene cial effects of mitochondria-targeting drugs in other clinical contexts 10,11 , such as autoimmunity [12][13][14] , although the concomitant disruption of the metagenome and increased risk of antibiotic resistance may limit their application to these conditions.…”