MyD88 Plays a Critical T Cell-Intrinsic Role in Supporting CD8 T Cell Expansion during Acute Lymphocytic Choriomeningitis Virus Infection

Rahman, Adeeb; Cui, Weiguo; LaRosa, David F.; Taylor, Daniel D.; Zhang, Jidong; Goldstein, Daniel R.; Wherry, E. John; Kaech, Susan M.; Turka, Laurence A.

doi:10.4049/jimmunol.181.6.3804

Cited by 71 publications

(105 citation statements)

References 31 publications

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“…Using adoptive transfer systems, we and others have previously shown that MyD88 expression in T cells is critical for regulating the size of the resulting memory population after acute viral infection. [4][5][6] Our initial experiments with T cell-specific Myd88-deficient mice confirmed these observations, showing that in the absence of MyD88 expression in T cells, LCMV infection induced significantly smaller populations of effector and memory cells. We further confirmed these results using cKO mice in which tamoxifen treatment deletes MyD88 expression before viral infection.…”

Section: Discussionsupporting

confidence: 67%

“…We found that the majority of YFP ϩ cells in cKO mice still lacked MyD88 expression, indicating that the memory T-cell response in cKO mice did not merely reflect preferential expansion of MyD88-sufficient cells ( Figure 6D). Because we have previously reported increased apoptosis in Myd88 Ϫ/Ϫ effector cells during primary expansion in response to LCMV, 6 we also examined the survival of LCMV-specific T cells after secondary expansion. Consistent with their comparable expansion, we found no notable differences in the apoptosis of YFP ϩ np396-specific cells in cKO and cHet mice either directly ex vivo or after in vitro culture ( Figure 6E).…”

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confidence: 99%

“…12 To validate the use of this system, we first verified that conditional deletion of MyD88 in naive T cells using Myd88 flox/flox mice produced results consistent with our earlier findings of reduced effector CD8 T-cell survival and accumulation using germline Myd88 Ϫ/Ϫ mice. 6 We therefore crossed Myd88 flox/flox mice with mice expressing Cre recombinase under the CD4 promoter. In the resulting mice, which we will subsequently refer to as Myd88⌬T mice, MyD88 expression is selectively deleted in all ␣␤T cells on the basis of Cre expression starting at the CD4 ϩ CD8 ϩ double-positive stage of thymocyte development ( Figure 1A).…”

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confidence: 99%

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Antiviral memory CD8 T-cell differentiation, maintenance, and secondary expansion occur independently of MyD88

Rahman

Zhang

Blosser

et al. 2011

Blood

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Inflammatory signals induced during infection regulate T-cell expansion, differentiation, and memory formation. Toll-like receptors (TLRs) are inflammatory mediators that allow innate immune cells to recognize and respond to invading pathogens. In addition to their role in innate immune cells, we have found that signals delivered through the TLR adapter protein myeloid differentiation protein 88 (MyD88) play a critical, T cell-intrinsic role in supporting the survival and accumulation of antigen-specific effector cells after acute viral infection. However, the importance of MyD88-dependent signals in regulating the generation and maintenance of memory T cells remained unclear. To address this, we used a novel, inducible knockout system to examine whether MyD88 is required for optimal memory CD8 T-cell generation and responses after lymphocytic choriomeningitis virus infection. We show that whereas MyD88 is critical for initial T-cell expansion, it is not required for the subsequent differentiation and stable mainte- IntroductionDuring acute viral infection, naive CD8 T cells undergo an initial phase of expansion and differentiation into functional effectors that play an integral role in viral clearance. The expansion phase is typically followed by a period of contraction, during which time the majority of effector T cells undergo apoptosis, and the remaining virus-specific T cells persist as a stable memory population that differs both phenotypically and functionally from the naive T-cell population. These memory CD8 T cells can rapidly differentiate into secondary effectors on subsequent reinfection and confer long-lasting, protective immunity. Thus, developing a better understanding of the signals that regulate the generation, maintenance, and reactivation of memory T cells is central to rational vaccine design.Myeloid differentiation protein 88 (MyD88) is an adaptor protein that is required for signal transduction through most Toll-like receptors (TLRs), as well as the interleukin-1 receptor (IL-1R) family. 1 TLR ligands that are released during infection are known agonists of MyD88-dependent pathways in innate immune cells, inducing activation, costimulatory molecule up-regulation, and inflammatory cytokine production, which serve to promote effective adaptive immune responses. 2,3 In addition to this indirect role, we and others have shown previously that MyD88 plays a critical, T cell-intrinsic role in regulating the survival and accumulation of antigen-specific effector T cells after acute viral infection. [4][5][6] Specifically, in the absence of MyD88, the number of effector CD8 T cells at the peak of the response and the number of antigen-specific memory T cells that persist are greatly reduced. It is well-established that the magnitude of the initial clonal burst significantly influences the size of the resulting memory T-cell compartment, 7 suggesting that the reduced number of memory cells that develop in the absence of MyD88 may be a secondary outcome of the role of MyD88 in controlling naive T-ce...

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Section: Discussionsupporting

confidence: 67%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Antiviral memory CD8 T-cell differentiation, maintenance, and secondary expansion occur independently of MyD88

Rahman

Zhang

Blosser

et al. 2011

Blood

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“…For instance, NKT cells may be affected directly, through TCR recognition of foreign-lipid Ags presented by CD1d molecules on the surface of an APC (18,19,(41)(42)(43), or indirectly, via presentation of endogenous lipids and production of cytokines, such as IL-12 and IL-18, by APCs upon TLR-induced activation (44,45). It is also possible that NKT cells may be directly activated through cell-intrinsic recognition of TLR agonists, a phenomenon recently suggested for conventional CD8 T cells (46). That heat-killed M. tuberculosis is the active component of CFA and contains several TLR2 agonists (47,48) suggests that CFA may activate NKT cells through a TCRindependent, TLR-dependent pathway.…”

Section: Nkt Cell Activation By Cfa Is Independent Of Myd88mentioning

confidence: 99%

NKT Cells Are Required for Complete Freund’s Adjuvant-Mediated Protection from Autoimmune Diabetes

Lee

Elzen

Tan

et al. 2011

The Journal of Immunology

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Autoimmune diabetes in NOD mice can be prevented by application of Ags derived from Mycobacterium tuberculosis in the form of bacillus Calmette-Guérin or CFA. Disease protection by CFA is associated with a reduction in the numbers of pathogenic β-cell specific, self-reactive CTLs, a phenomenon dependent on the presence and function of NK cells. However, the mechanisms by which NK cells are activated and recruited by heat-killed M. tuberculosis within CFA are unclear. In this study, we report that CFA-mediated NK cell activation and mobilization is dependent on CD1d expression. The administration of M. tuberculosis from CFA results in rapid NKT cell activation and IFN-γ secretion both in vitro and in vivo. CFA-induced NKT cell activation is intact in MyD88−/− mice suggesting that the mechanism is independent of TLR signaling. Furthermore, CD1d expression was found to be essential for both M. tuberculosis-triggered NKT cell activation and CFA-mediated protection of NOD mice from diabetes. Collectively, these findings reveal hitherto previously unidentified roles for NKT cells in the adjuvant-promoting effects of CFA on innate and adaptive immunity.

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“…However, a strong innate immune response is important for the generation of an effective adaptive response against viral infections (Jung, Kato et al 2008;Rahman, Cui et al 2008;Zucchini, Bessou et al 2008). Moreover, DCs are indispensible for the generation of the CD8+ effector T cells.…”

Section: Chronic Viral Infections Inhibit Innate and Dendritic Cell Rmentioning

confidence: 99%

Viruses Strive to Suppress Host Immune Responses and Prolong Persistence

Pritzl¹,

Seo²,

Hahm³

2012

Recent Advances in Immunology to Target Cancer, Inflammation and Infections

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MyD88 Plays a Critical T Cell-Intrinsic Role in Supporting CD8 T Cell Expansion during Acute Lymphocytic Choriomeningitis Virus Infection

Cited by 71 publications

References 31 publications

Antiviral memory CD8 T-cell differentiation, maintenance, and secondary expansion occur independently of MyD88

Antiviral memory CD8 T-cell differentiation, maintenance, and secondary expansion occur independently of MyD88

NKT Cells Are Required for Complete Freund’s Adjuvant-Mediated Protection from Autoimmune Diabetes

Viruses Strive to Suppress Host Immune Responses and Prolong Persistence

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