scholarly journals T cell responses in calcineurin A alpha-deficient mice.

1996 ◽  
Vol 183 (2) ◽  
pp. 413-420 ◽  
Author(s):  
B W Zhang ◽  
G Zimmer ◽  
J Chen ◽  
D Ladd ◽  
E Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Es Cells ◽  
Embryonic Stem ◽  
T Cell Responses ◽  
T Cell Response ◽  
Cell Responses ◽  
Calcineurin A

We have created embryonic stem (ES) cells and mice lacking the predominant isoform (alpha) of the calcineurin A subunit (CNA alpha) to study the role of this serine/threonine phosphatase in the immune system. T and B cell maturation appeared to be normal in CNA alpha -/- mice. CNA alpha -/- T cells responded normally to mitogenic stimulation (i.e., PMA plus ionomycin, concanavalin A, and anti-CD3 epsilon antibody). However, CNA alpha -/- mice generated defective antigen-specific T cell responses in vivo. Mice produced from CNA alpha -/- ES cells injected into RAG-2-deficient blastocysts had a similar defective T cell response, indicating that CNA alpha is required for T cell function per se, rather than for an activity of other cell types involved in the immune response. CNA alpha -/- T cells remained sensitive to both cyclosporin A and FK506, suggesting that CNA beta or another CNA-like molecule can mediate the action of these immunosuppressive drugs. CNA alpha -/- mice provide an animal model for dissecting the physiologic functions of calcineurin as well as the effects of FK506 and CsA.

scholarly journals Immune Responses in Perforin Deficient Mice

2021 ◽  
Author(s):  
◽  
Helen Mary Alys Simkins
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Influenza Infection ◽  
T Cell Responses ◽  
Nkt Cells ◽  
T Cell Response ◽  
Dependent Manner ◽  
Cell Responses

<p>Dendritic cells (DC) play a pivotal role in the initiation of T cell responses and earlier studies have shown that their survival is important for the generation of effective immune responses. Cytotoxic T lymphocytes (CTL) and natural killer T (NKT) cells have been proposed to regulate the survival of antigen presenting DC through their ability to kill cells expressing specific antigen via secretion of perforin, a protein contained in cytotoxic granules. Perforin knockout (PKO) mice generate amplified immune responses to DC immunization, suggesting a link between defective cytotoxicity and increased T cell responses. The studies in this thesis used PKO mice and in vivo models of CD8+T cells and NKT cell immune responses to determine whether CTL and NKT cells eliminate DC in a perforin-dependent manner, and whether DC elimination is a mechanism to regulate T cell responses. During a primary influenza infection C57BL/6 and PKO mice generated a similar influenza specific CD8+ immune response. No significant difference in the percentage of influenza epitope PA224-233 specific T cells was observed between C57BL/6 and PKO mice during a secondary influenza infection, but PKO mice had a significantly reduced T cell response directed towards the dominant influenza epitope, NP366-374. The reduced T cell response in PKO mice was not due to differences in activation or differentiation status of specific T cells compared to C57BL/6 mice. Therefore, the extended DC survival in PKO after secondary influenza viral infection, recently reported by other authors, does not appear to correlate with increased expansion of virus specific CD8+T cells in infected mice. The role of NKT cells in DC elimination was assessed in vivo using the NKT cell ligand a-Galactosylceramide (a-GalCer). Injection of a-GalCer in C57BL/6 mice induced a dramatic decline in the number of splenic CD8+DC. A similar decrease in CD8+DC numbers was observed in PKO mice, suggesting that the mechanism of DC loss did not involve perforinmediated killing. In contrast, treatment with a TNF-a neutralizing antibody substantially reduced the decline in CD8+DC numbers. This reduction in splenic CD8+DC occurred as early as 15 hr after a-GalCer treatment, and did not affect generation of CD8+T cell responses or the ability of a-GalCer treatment to provide tumour protection. Taken together, these results suggest that multiple cells and mechanisms can regulate DC survival in vivo. CTL regulate DC survival in vivo in a perforin-dependent manner, but this does not necessarily affect the magnitude of the resulting immune responses. NKT cells also affect the survival of DC in vivo, but in a perforin-independent, cytokine-dependent manner. These findings provide additional knowledge about the in vivo involvement of perforin in regulating DC survival by CTL and NKT cells and the effects this has on T cell responses.</p>

scholarly journals Immune Responses in Perforin Deficient Mice

2021 ◽  
Author(s):  
◽  
Helen Mary Alys Simkins
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Influenza Infection ◽  
T Cell Responses ◽  
Nkt Cells ◽  
T Cell Response ◽  
Dependent Manner ◽  
Cell Responses

<p>Dendritic cells (DC) play a pivotal role in the initiation of T cell responses and earlier studies have shown that their survival is important for the generation of effective immune responses. Cytotoxic T lymphocytes (CTL) and natural killer T (NKT) cells have been proposed to regulate the survival of antigen presenting DC through their ability to kill cells expressing specific antigen via secretion of perforin, a protein contained in cytotoxic granules. Perforin knockout (PKO) mice generate amplified immune responses to DC immunization, suggesting a link between defective cytotoxicity and increased T cell responses. The studies in this thesis used PKO mice and in vivo models of CD8+T cells and NKT cell immune responses to determine whether CTL and NKT cells eliminate DC in a perforin-dependent manner, and whether DC elimination is a mechanism to regulate T cell responses. During a primary influenza infection C57BL/6 and PKO mice generated a similar influenza specific CD8+ immune response. No significant difference in the percentage of influenza epitope PA224-233 specific T cells was observed between C57BL/6 and PKO mice during a secondary influenza infection, but PKO mice had a significantly reduced T cell response directed towards the dominant influenza epitope, NP366-374. The reduced T cell response in PKO mice was not due to differences in activation or differentiation status of specific T cells compared to C57BL/6 mice. Therefore, the extended DC survival in PKO after secondary influenza viral infection, recently reported by other authors, does not appear to correlate with increased expansion of virus specific CD8+T cells in infected mice. The role of NKT cells in DC elimination was assessed in vivo using the NKT cell ligand a-Galactosylceramide (a-GalCer). Injection of a-GalCer in C57BL/6 mice induced a dramatic decline in the number of splenic CD8+DC. A similar decrease in CD8+DC numbers was observed in PKO mice, suggesting that the mechanism of DC loss did not involve perforinmediated killing. In contrast, treatment with a TNF-a neutralizing antibody substantially reduced the decline in CD8+DC numbers. This reduction in splenic CD8+DC occurred as early as 15 hr after a-GalCer treatment, and did not affect generation of CD8+T cell responses or the ability of a-GalCer treatment to provide tumour protection. Taken together, these results suggest that multiple cells and mechanisms can regulate DC survival in vivo. CTL regulate DC survival in vivo in a perforin-dependent manner, but this does not necessarily affect the magnitude of the resulting immune responses. NKT cells also affect the survival of DC in vivo, but in a perforin-independent, cytokine-dependent manner. These findings provide additional knowledge about the in vivo involvement of perforin in regulating DC survival by CTL and NKT cells and the effects this has on T cell responses.</p>

scholarly journals Designing Strategies to Improve the T Cell  Mediated Immunotherapy of Mouse Tumours.

2021 ◽  
Author(s):  
◽  
Haley Ataera
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Tumour Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Full Potential ◽  
Activation Markers ◽  
Cell Responses

<p>The adoptive transfer of activated dendritic cells (DC) loaded with tumour antigen or tumour specific T cells improves weak anti-tumour responses, however, without treatments to relieve suppression, these therapies will continue to fall short of their full potential. The aim of this thesis was to understand the role of hypoxia-induced increases in adenosine and of CD4+ CD25+ Foxp3+ regulatory T cells (Treg) in the suppression of anti-tumour immune responses and to design strategies to abrogate these mechanisms. These aims were investigated using the B16.OVA murine melanoma model because the OVA specific CD4+ (OTII) and CD8+ (OTI) T cell transgenic mice allowed detailed investigation of Ag specific T cell responses. Recent studies have shown that the inhibition of adenosine signalling in activated CD8+ T cells can improve the anti-tumour activity of these cells. To investigate these findings using the B16.OVA model, tumour-bearing mice were given activated OTI T cells and the adenosine receptor inhibitor caffeine. Caffeine treatment did not improve the anti-tumour response, possibly because this response was suppressed due to the increased frequency of myeloid derived suppressor cells observed in mice that received T cells. To determine whether the defective function of tumour infiltrating DC (TIDC) in tumours is due to suppression by Treg, mice were treated with the anti-CD25 monoclonal antibody PC61 to deplete Treg and challenged with tumours. PC61 treatment caused a delay in tumour growth but did not affect DC frequency, or expression of the DC activation markers CD40, CD86 and MHC II in tumours or lymph nodes. DC function was tested using in vitro and in vivo T cell proliferation assays and was found to be unaffected by PC61 treatment. Studies in RAG1-/- mice, which lack Treg, also showed no improvement in DC activation status or function. These results show that Treg do not suppress TIDC in the B16.OVA model. It is well known, however, that Treg suppress T cell responses and it has been suggested that Treg may mediate some of this suppression by using the perforin-granzyme pathway to cause T cell death. To investigate this possibility, naive, perforin sufficient OTI T cells were transferred into normal and perforin knockout (PKO) mice, with or without PC61 treatment. To stimulate an OTI T cell response, mice also received OVA-loaded DC. Depletion of both normal and PKO Treg resulted in decreased death and increased proliferation of the transferred cells, increased expression of IFN-y and TNF-a, and improved in vivo target cell killing by the transferred cells. These findings indicate that perforin expression by Treg is not required to suppress T cell responses or cause T cell death. In conclusion, the results of this thesis were consistent with the observation that there are multiple suppressive mechanisms in tumours and that there is substantial redundancy of these mechanisms. Depletion of Treg was found to improve the anti-tumour response, however, suppression of the DC was still evident, demonstrating that the neutralisation of a single suppressive mechanism may not be sufficient to treat aggressive, late stage cancers such as melanoma.</p>

scholarly journals Thymic stromal lymphopoietin limits primary and recall CD8+ T-cell anti-viral responses

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Risa Ebina-Shibuya ◽  
Erin E West ◽  
Rosanne Spolski ◽  
Peng Li ◽  
Jangsuk Oh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cell Function ◽  
Influenza Infection ◽  
T Cell Responses ◽  
T Cell Response ◽  
Thymic Stromal Lymphopoietin ◽  
Direct Role ◽  
Cell Responses

Thymic stromal lymphopoietin (TSLP) is a cytokine that acts directly on CD4+ T cells and dendritic cells to promote progression of asthma, atopic dermatitis, and allergic inflammation. However, a direct role for TSLP in CD8+ T-cell primary responses remains controversial and its role in memory CD8+ T cell responses to secondary viral infection is unknown. Here, we investigate the role of TSLP in both primary and recall responses in mice using two different viral systems. Interestingly, TSLP limited the primary CD8+ T-cell response to influenza but did not affect T cell function nor significantly alter the number of memory CD8+ T cells generated after influenza infection. However, TSLP inhibited memory CD8+ T-cell responses to secondary viral infection with influenza or acute systemic LCMV infection. These data reveal a previously unappreciated role for TSLP on recall CD8+ T-cell responses in response to viral infection, findings with potential translational implications.

scholarly journals CD4+CD25+ T Cells Regulate Virus-specific Primary and Memory CD8+ T Cell Responses

2003 ◽  
Vol 198 (6) ◽  
pp. 889-901 ◽  
Author(s):  
Susmit Suvas ◽  
Uday Kumaraguru ◽  
Christopher D. Pack ◽  
Sujin Lee ◽  
Barry T. Rouse
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cell Function ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Reactivity ◽  
Cell Responses

Naturally occurring CD4+CD25+ regulatory T cells appear important to prevent activation of autoreactive T cells. This article demonstrates that the magnitude of a CD8+ T cell–mediated immune response to an acute viral infection is also subject to control by CD4+CD25+ T regulatory cells (Treg). Accordingly, if natural Treg were depleted with specific anti-CD25 antibody before infection with HSV, the resultant CD8+ T cell response to the immunodominant peptide SSIEFARL was significantly enhanced. This was shown by several in vitro measures of CD8+ T cell reactivity and by assays that directly determine CD8+ T cell function, such as proliferation and cytotoxicity in vivo. The enhanced responsiveness in CD25-depleted animals was between three- and fourfold with the effect evident both in the acute and memory phases of the immune response. Surprisingly, HSV infection resulted in enhanced Treg function with such cells able to suppress CD8+ T cell responses to both viral and unrelated antigens. Our results are discussed both in term of how viral infection might temporarily diminish immunity to other infectious agents and their application to vaccines. Thus, controlling suppressor effects at the time of vaccination could result in more effective immunity.

scholarly journals Designing Strategies to Improve the T Cell  Mediated Immunotherapy of Mouse Tumours.

2021 ◽  
Author(s):  
◽  
Haley Ataera
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Tumour Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Full Potential ◽  
Activation Markers ◽  
Cell Responses

<p>The adoptive transfer of activated dendritic cells (DC) loaded with tumour antigen or tumour specific T cells improves weak anti-tumour responses, however, without treatments to relieve suppression, these therapies will continue to fall short of their full potential. The aim of this thesis was to understand the role of hypoxia-induced increases in adenosine and of CD4+ CD25+ Foxp3+ regulatory T cells (Treg) in the suppression of anti-tumour immune responses and to design strategies to abrogate these mechanisms. These aims were investigated using the B16.OVA murine melanoma model because the OVA specific CD4+ (OTII) and CD8+ (OTI) T cell transgenic mice allowed detailed investigation of Ag specific T cell responses. Recent studies have shown that the inhibition of adenosine signalling in activated CD8+ T cells can improve the anti-tumour activity of these cells. To investigate these findings using the B16.OVA model, tumour-bearing mice were given activated OTI T cells and the adenosine receptor inhibitor caffeine. Caffeine treatment did not improve the anti-tumour response, possibly because this response was suppressed due to the increased frequency of myeloid derived suppressor cells observed in mice that received T cells. To determine whether the defective function of tumour infiltrating DC (TIDC) in tumours is due to suppression by Treg, mice were treated with the anti-CD25 monoclonal antibody PC61 to deplete Treg and challenged with tumours. PC61 treatment caused a delay in tumour growth but did not affect DC frequency, or expression of the DC activation markers CD40, CD86 and MHC II in tumours or lymph nodes. DC function was tested using in vitro and in vivo T cell proliferation assays and was found to be unaffected by PC61 treatment. Studies in RAG1-/- mice, which lack Treg, also showed no improvement in DC activation status or function. These results show that Treg do not suppress TIDC in the B16.OVA model. It is well known, however, that Treg suppress T cell responses and it has been suggested that Treg may mediate some of this suppression by using the perforin-granzyme pathway to cause T cell death. To investigate this possibility, naive, perforin sufficient OTI T cells were transferred into normal and perforin knockout (PKO) mice, with or without PC61 treatment. To stimulate an OTI T cell response, mice also received OVA-loaded DC. Depletion of both normal and PKO Treg resulted in decreased death and increased proliferation of the transferred cells, increased expression of IFN-y and TNF-a, and improved in vivo target cell killing by the transferred cells. These findings indicate that perforin expression by Treg is not required to suppress T cell responses or cause T cell death. In conclusion, the results of this thesis were consistent with the observation that there are multiple suppressive mechanisms in tumours and that there is substantial redundancy of these mechanisms. Depletion of Treg was found to improve the anti-tumour response, however, suppression of the DC was still evident, demonstrating that the neutralisation of a single suppressive mechanism may not be sufficient to treat aggressive, late stage cancers such as melanoma.</p>

scholarly journals Kinetics and Phenotype of Vaccine-Induced CD8+ T-Cell Responses to Toxoplasma gondii

2009 ◽  
Vol 77 (9) ◽  
pp. 3894-3901 ◽  
Author(s):  
Kimberly A. Jordan ◽  
Emma H. Wilson ◽  
Elia D. Tait ◽  
Barbara A. Fox ◽  
David S. Roos ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Critical Role ◽  
T Cell Responses ◽  
Cytolytic Activity ◽  
Effector T Cells ◽  
T Cell Response ◽  
Cell Responses

ABSTRACT Multiple studies have established that the ability of CD8+ T cells to act as cytolytic effectors and produce gamma interferon is important in mediating resistance to the intracellular parasite Toxoplasma gondii. To better understand the generation of the antigen-specific CD8+ T-cell responses induced by T. gondii, mice were immunized with replication-deficient parasites that express the model antigen ovalbumin (OVA). Class I tetramers specific for SIINFEKL were used to track the OVA-specific endogenous CD8+ T cells. The peak CD8+ T-cell response was found at day 10 postimmunization, after which the frequency and numbers of antigen-specific cells declined. Unexpectedly, replication-deficient parasites were found to induce antigen-specific cells with faster kinetics than replicating parasites. The generation of optimal numbers of antigen-specific CD8+ effector T cells was found to require CD4+ T-cell help. At 7 days following immunization, antigen-specific cells were found to be CD62Llow, KLRG1+, and CD127low, and they maintained this phenotype for more than 70 days. Antigen-specific CD8+ effector T cells in immunized mice exhibited potent perforin-dependent OVA-specific cytolytic activity in vivo. Perforin-dependent cytolysis appeared to be the major cytolytic mechanism; however, a perforin-independent pathway that was not mediated via Fas-FasL was also detected. This study provides further insight into vaccine-induced cytotoxic T-lymphocyte responses that correlate with protective immunity to T. gondii and identifies a critical role for CD4+ T cells in the generation of protective CD8+ T-cell responses.

scholarly journals Role of Thymic Output in Regulating CD8 T-Cell Homeostasis during Acute and Chronic Viral Infection

2005 ◽  
Vol 79 (15) ◽  
pp. 9419-9429 ◽  
Author(s):  
Nicole E. Miller ◽  
Jennifer R. Bonczyk ◽  
Yumi Nakayama ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Viral Infections ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
Lcmv Infection

ABSTRACT Although it is well documented that CD8 T cells play a critical role in controlling chronic viral infections, the mechanisms underlying the regulation of CD8 T-cell responses are not well understood. Using the mouse model of an acute and chronic lymphocytic choriomeningitis virus (LCMV) infection, we have examined the relative importance of peripheral T cells and thymic emigrants in the elicitation and maintenance of CD8 T-cell responses. Virus-specific CD8 T-cell responses were compared between mice that were either sham thymectomized or thymectomized (Thx) at ∼6 weeks of age. In an acute LCMV infection, thymic deficiency did not affect either the primary expansion of CD8 T cells or the proliferative renewal and maintenance of virus-specific lymphoid and nonlymphoid memory CD8 T cells. Following a chronic LCMV infection, in Thx mice, although the initial expansion of CD8 T cells was normal, the contraction phase of the CD8 T-cell response was exaggerated, which led to a transient but striking CD8 T-cell deficit on day 30 postinfection. However, the virus-specific CD8 T-cell response in Thx mice rebounded quickly and was maintained at normal levels thereafter, which indicated that the peripheral T-cell repertoire is quite robust and capable of sustaining an effective CD8 T-cell response in the absence of thymic output during a chronic LCMV infection. Taken together, these findings should further our understanding of the regulation of CD8 T-cell homeostasis in acute and chronic viral infections and might have implications in the development of immunotherapy.

scholarly journals Convergent epitope-specific T cell responses after SARS-CoV-2 infection and vaccination

2021 ◽  
Author(s):  
Anastasia A Minervina ◽  
Mikhail V Pogorelyy ◽  
Allison M Kirk ◽  
Emma Kaitlynn Allen ◽  
Kim J Allison ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
T Cell Response ◽  
Critical Parameters ◽  
T Cell Memory ◽  
Cell Memory ◽  
Cell Responses ◽  
Depth Analysis

SARS-CoV-2 mRNA vaccines, including Pfizer/Biontech BNT162b2, were shown to be effective for COVID-19 prevention, eliciting both robust antibody responses in naive individuals and boosting pre-existing antibody levels in SARS-CoV-2-recovered individuals. However, the magnitude, repertoire, and phenotype of epitope-specific T cell responses to this vaccine, and the effect of vaccination on pre-existing T cell memory in SARS-CoV-2 convalescent patients, are still poorly understood. Thus, in this study we compared epitope-specific T cells elicited after natural SARS-CoV-2 infection, and vaccination of both naive and recovered individuals. We collected peripheral blood mononuclear cells before and after BNT162b2 vaccination and used pools of 18 DNA-barcoded MHC-class I multimers, combined with scRNAseq and scTCRseq, to characterize T cell responses to several immunodominant epitopes, including a spike-derived epitope cross-reactive to common cold coronaviruses. Comparing responses after infection or vaccination, we found that T cells responding to spike-derived epitopes show similar magnitudes of response, memory phenotypes, TCR repertoire diversity, and αβTCR sequence motifs, demonstrating the potency of this vaccination platform. Importantly, in COVID-19-recovered individuals receiving the vaccine, pre-existing spike-specific memory cells showed both clonal expansion and a phenotypic shift towards more differentiated CCR7-CD45RA+ effector cells. In-depth analysis of T cell receptor repertoires demonstrates that both vaccination and infection elicit largely identical repertoires as measured by dominant TCR motifs and receptor breadth, indicating that BNT162b2 vaccination largely recapitulates T cell generation by infection for all critical parameters. Thus, BNT162b2 vaccination elicits potent spike-specific T cell responses in naive individuals and also triggers the recall T cell response in previously infected individuals, further boosting spike-specific responses but altering their differentiation state. Overall, our study demonstrates the potential of mRNA vaccines to induce, maintain, and shape T cell memory through vaccination and revaccination.

scholarly journals Adrenergic signaling controls early transcriptional programs during CD8+ T cell responses to viral infection

2021 ◽  
Author(s):  
Leonardo Estrada ◽  
Didem Agac Cobanoglu ◽  
Aaron Wise ◽  
Robert Maples ◽  
Murat Can Cobanoglu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Receptor Activation ◽  
Cell Development ◽  
Primary Response ◽  
Cell Responses

Viral infections drive the expansion and differentiation of responding CD8+ T cells into variegated populations of cytolytic effector and memory cells. While pro-inflammatory cytokines and cell surface immune receptors play a key role in guiding T cell responses to infection, T cells are also markedly influenced by neurotransmitters. Norepinephrine is a key sympathetic neurotransmitter, which acts to suppress CD8 + T cell cytokine secretion and lytic activity by signaling through the beta2-adrenergic receptor (ADRB2). Although ADRB2 signaling is considered generally immunosuppressive, its role in regulating differentiation of effector T cells in response to infection has not been investigated. Using an adoptive transfer approach, we compared the expansion and differentiation of wild type (WT) to Adrb2-/- CD8 + T cells throughout the primary response to vesicular stomatitis virus (VSV) infection in vivo. We measured the dynamic changes in transcriptome profiles of antigen-specific CD8 + T cells as they responded to VSV. Within the first 7 days of infection, WT cells out-paced the expansion of Adrb2-/- cells, which correlated with reduced expression of IL-2 and the IL-2Ralpha; in the absence of ADRB2. RNASeq analysis identified over 300 differentially expressed genes that were both temporally regulated following infection and selectively regulated in WT vs Adrb2-/- cells. These genes contributed to major transcriptional pathways including cytokine receptor activation, signaling in cancer, immune deficiency, and neurotransmitter pathways. By parsing genes within groups that were either induced or repressed over time in response to infection, we identified three main branches of genes that were differentially regulated by the ADRB2. These gene sets were predicted to be regulated by specific transcription factors involved in effector T cell development, such as Tbx21 and Eomes. Collectively, these data demonstrate a significant role for ADRB2 signaling in regulating key transcriptional pathways during CD8 + T cells responses to infection that may dramatically impact their functional capabilities and downstream memory cell development.

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