Chemokine Signatures Of Pathogen-Specific T Cells I: Effector T Cells

Abstract

The choreography of complex immune responses, including the priming, differentiation, and modulation of specific effector T cell populations generated in the immediate wake of an acute pathogen challenge, is in part controlled by chemokines, a large family of mostly secreted molecules involved in chemotaxis and other patho/physiological processes. T cells are both responsive to varied chemokine cues and a relevant source for certain chemokines themselves. Yet the actual range, regulation, and role of effector T cell-derived chemokines remains incompletely understood. Here, using different in vivo models of viral and bacterial infection as well as protective vaccination, we have defined the entire spectrum of chemokines produced by pathogen-specific CD8+ and CD4+T effector cells, and delineated several unique properties pertaining to the temporospatial organization of chemokine expression patterns, synthesis and secretion kinetics, and cooperative regulation. Collectively, our results position the “T cell chemokine response” as a notably prominent, largely invariant yet distinctive force at the forefront of pathogen-specific effector T cell activities, and establish novel practical and conceptual approaches that may serve as a foundation for future investigations into role of T cell-produced chemokines in infectious and other diseases.

Memory CD8+T cells mediate early pathogen-specific protection through localized delivery of chemokines and IFNγ to clusters of inflammatory monocytes

“…These results collectively indicate a direct correlation between the strength of TCR signaling and the proportion of chemokine-producing CD8 + T M cells. Furthermore, in vitro “challenge” of OT-I T M cells isolated from Lm- Ova-immunized mice with the SIINFKEL epitope in the presence or absence of broad inhibitors of either translation (cycloheximide) or transcription (Actinomycin D), suggested that most of the CCL3 in Ag- stimulated T M cells was being rapidly transcribed (>60%)(Figure 3D) while only a smaller proportion was stored as mRNA (∼30%) but none as protein, a result also consistent with recent reports (Davenport et al, 2020; Eberlein et al, 2020). Taken together, these data support the hypothesis that IRF4 acts as a transcriptional regulator of chemokine expression downstream of TCR signaling.…”

“…Another important finding in our study relates to the rapid, transcriptionally controlled and coordinated production of CCL3, CCL4 and XCL1 chemokines by CD8 + T M cells induced upon vaccination with both Lm and VSV in response to cognate Ag recognition. These results are consistent with two recent reports that utilized multiple models of acute and chronic infections, as well as ex vivo stimulation assays, and outline that the robust chemokine signature is a key and important feature of both Ag-stimulated effector and memory CD8 + T cells (Davenport et al, 2020; Eberlein et al, 2020). CD8 + T M cells undergoing repetitive in vivo stimulations were also reported to significantly upregulate genes encoding for these chemokines (Wirth et al, 2010).…”

Chemokine Signatures of Pathogen-Specific T Cells II: Memory T Cells in Acute and Chronic Infection

“…Importantly, in the same study, we provide detailed evidence that the induced production of all of the above (CCL1/3/4/5/9/10 and XCL1), but no other chemokines, constitutes a largely invariant functional signature of specific CD8 + and CD4 + T E generated in response to acute viral and bacterial infections, as well as protective immunization (34). Building on this work, we have now extended our investigations to an interrogation of the identities, patterns, regulation, and relevance of chemokines expressed by pathogen-specific T M populations maintained after resolution of acute and under conditions of chronic infections.…”

“…Other studies, however, have demonstrated a preferential association of constitutively expressed CCL5 with cytolytic granules in HIV-specific CD8 + T cell clones or primary (I˚) human CD8 + T cells (13,31), but murine memory-phenotype CD8 + T cells (CD8 + T MP ), which contain abundant Ccl5 in addition to Ccl3 and Ccl4 transcripts, apparently do not express the corresponding proteins, the synthesis of which requires TCR stimulation (32,33). Our recent work on chemokine signatures of pathogen-specific CD8 + T E may provide clues for a reconciliation of these discrepancies (34): at the peak of the effector response, CD8 + T E express constitutive CCL5 in a subcellular compartment distinct from granzyme (Gzm)-containing cytolytic granules, but upon TCR stimulation, these structures partly coalesce just prior to secretion; in fact, release of prestored CCL5 proceeds so rapidly that temporarily, and within the confines of the immunological synapse, CCL5 concentrations well in excess of 1 mM may be achieved (34), a potential foundation for in vivo CCL5 action at supraphysiological levels (16,17).…”

“…LCMV Armstrong (Arm; clone 53b) and clone 13 (cl13) were obtained from Dr. M. Oldstone, stocks were prepared by a single passage on BHK-21 cells, and plaque assays for determination of virus titers were performed as described (38). Recombinant Listeria monocytogenes expressing full-length OVA (rLM-OVA) (39) was grown and titrated as described (34,40). For acute infections, 8-10-wk-old mice were inoculated with a single i.p.…”