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Control of CD4 Helper and CD8 Cytotoxic T Cell Differentiation https://www.scientificarchives.com/journal/journal-of-cellular-immunology Journal of Cellular Immunology Commentary Control of CD4 Helper and CD8 Cytotoxic T cell Differentiation Vibhuti P Dave* Département d’Immunologie-Oncologie, Centre de Recherche Hôpital Maisonneuve-Rosemont, Montreal, Quebec H1T 2M4, Canada *Correspondence should be addressed to Vibhuti P Dave; [email protected] Received date: June 29, 2020, Accepted date: July 15, 2020 Copyright: © 2020 Dave VP. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Engagement of mature T cell receptor (TCR), a culminating in shorter or weaker signal transduction multiprotein complex consisting of an αβ heterodimer in MHCI-signaled thymocytes, while continued CD4 associated with invariant CD3 signaling proteins, on expression at this stage, and therefore higher Lck activity, CD4+CD8+ double positive (DP) thymocytes by self- results in sustained or stronger signal in MHCII-signaled peptide/self-MHC complex on thymic stromal cells thymocytes. However, two observations suggest that results in negative selection of thymocytes expressing kinetic signal strength model alone cannot explain the strong affinity TCRs and positive selection of thymocytes CD4 helper versus CD8 cytotoxic lineage choice; (a) expressing weak affinity TCRs. Positively selected constitutive CD8 or chimeric CD8.4 (cytoplasmic domain thymocytes almost invariably differentiate into MHCII- of CD8 substituted by that of CD4) redirects only a fraction specific CD4+ helper and MHCI-specific CD8+ cytotoxic T of MHCI-signaled thymocytes into CD4 lineage [14] and cells endowed with effector functions crucial for effective (b) positively selected MHCI-restricted thymocytes cell-mediated immune responses [1,2]. Together, thymic expressing strong affinity TCR such as OTI- TCR and P14- selection and lineage choice ensures generation of mature TCR, which transduce stronger signal compared to several T cell repertoire that is capable of mounting effective MHCII-specific TCRs such as OTII-TCR, fail to develop responses to non-self-antigens but is tolerant to self- into the CD4 helper lineage [15]. It is proposed that signal antigens encountered in the periphery [3,4]. Although disruption renders MHCI-signaled thymocytes sensitive correlation between MHC specificity with helper and to cytokine signaling critical for Runx3 activation and the cytotoxic lineage choice remains unclear, it appears to CD8 cytotoxic lineage choice [16,17], while stronger TCR be influenced by duration and intensity of TCR signaling signal induces ThPOK (Zbtb7b, cKrox) in MHCII- signal that imprints transcriptional program underlying the thymocytes essential for the CD4 helper lineage choice two lineages [5]. Specificity of CD4 and CD8 coreceptor [18]. Identification of Helper Deficient (HD) mouse and for MHCII and MHCI, respectively, is important in TCR subsequent research showed that loss and gain of ThPOK signaling with CD4, compared to CD8, promoting stronger function redirects, respectively, MHCII-specific cells signaling due to stronger association of Src tyrosine kinase into the CD8 cytotoxic lineage and MHCI-specific cells Lck with cytoplasmic tail of CD4 than that of CD8 [6-10]. into the CD4 helper lineage [19-22]. In contrast, Runx3 Irrespective of MHC specificity positively selected DP deficiency or constitutive expression alters lineage choice thymocytes temporally downregulate Cd8 transcription of only a fraction of MHCI-signaled thymocytes [23-26]. and become CD4+CD8lo thymocytes that eventually Collectively, these observations suggest a dominant role develop into CD4+ and CD8+ single positive (SP) mature for ThPOK in the CD4 helper versus CD8 cytotoxic lineage thymocytes [3,11]. Indeed, ablating CD4 expression at choice of developing thymocytes. CD4+CD8lo stage redirects positively selected thymocytes into the cytotoxic lineage [12]. Thus, kinetics of coreceptor, Although MHC specificity of positively selected thymocytes particularly CD4, expression plays an important role in CD4 correlates with functionally distinct lineages, cellular vs CD8 lineage choice. Based on these observations kinetic components associated with proximal TCR signaling signal strength model has been proposed for CD4/CD8 are similar except for stronger Lck association with the lineage choice [13]. Accordingly, in CD4+CD8lo thymocytes cytoplasmic tail of CD4 than that of CD8. However, higher downregulation of CD8 results in reduced Lck activity Lck activity in MHCII-signaled cells alone cannot explain J Cell Immunol. 2020 Volume 2, Issue 5 220 Dave VP. Control of CD4 Helper and CD8 Cytotoxic T cell Differentiation. J Cell Immunol. 2020; 2(5): 220-226. CD4 lineage choice as constitutively active or dominant developing thymocytes [33,34]. Our subsequent analysis negative Lck alters lineage fate of only a small number showed that the same ThPOK transgene completely of positively selected thymocytes expressing monoclonal restores CD4 development of MHCII-specific OTII-TCR in TCR [8,9]. Similarly, temporal and differential kinetics of Thpok-/- mice providing first indication that, compared to ZAP70 expression, delayed and higher expression in the MHCII-signaled thymocytes, MHCI-signaled thymocytes CD8 compared to CD4 committed thymocytes, is proposed require significantly higher amount of ThPOK for efficient to play a role in lineage divergence although mechanism CD4 lineage choice. Further experimentations showed of its action remains undefined [5,27-29]. How differences that augmenting TCR signal strength via introduction of in kinetics and/or strength of proximal TCR signaling constitutively active Lck increases the efficiency of ThPOK- lead to activation of lineage specifying ThPOK and Runx3 induced CD4 lineage choice of MHCI-specific thymocytes expression in MHCII- and MHCI-signaled thymocytes, although it was still lower compared to the CD4 lineage respectively, is challenging and remains to be elucidated. choice of MHCII-signaled thymocytes expressing the same amount of ThPOK. Together these analyses suggest that Central role for ThPOK in defining the CD4 versus CD8 suppression of cytotoxic and induction of helper program lineage divergence has prompted intense investigation require different amount of ThPOK, and strength and of this BTB/POZ zinc finger transcription factor over the quality of TCR signaling largely determines the efficiency last decade. Previous studies showed that constitutive of ThPOK-induced CD4 lineage choice. ThPOK expression redirects MHCI-signaled thymocytes into the CD4 helper lineage [20,30]; however it remained How might TCR signal strength and MHC specificity unclear if a defined amount of ThPOK promoted the CD4 segregate CD4 versus CD8 lineage choice? Mechanistically lineage choice of MHCI- and MHCII-signaled thymocytes there are two mutually nonexclusive possibilities that may at comparable efficiency and whether TCR signal strength underlie differential impact of a defined amount of ThPOK or MHC specificity played any role in this process. In our on lineage choice. It is conceivable that during a temporal recently published article, we evaluated role of ThPOK window of lineage choice [35], accessibility of genes dose and TCR signal strength on the CD4 lineage choice regulated by ThPOK or Runx3 is influenced by strength of MHCI- and MHCII-signaled thymocytes [31]. Analysis and duration of TCR signaling; stronger and longer of three independent transgenic mouse lines expressing duration of TCR signal in MHCII-signaled thymocytes different amounts of ThPOK in developing thymocytes may permit target gene loci access for an extended period showed that the efficiency of CD4 lineage choice of MHCI- requiring a smaller amount of ThPOK for modulating their signaled thymocytes expressing monoclonal (OTI- and expression leading to suppression of cytotoxic program P14-TCR) or polyclonal (MHCII-/- mice) TCR specificities and induction of helper program. Conversely, TCR was directly proportional to ThPOK levels in the signal disruption in MHCI-signaled thymocytes reduced preselection DP thymocytes. These data suggest the extent accessibility of target genes would require significantly of transgenic ThPOK occupancy at the target gene loci more ThPOK (than the amount required for CD4 lineage may prime positively selected MHCI-signaled thymocytes choice of MHCII-signaled thymocytes) for the CD4 for the CD4 lineage development. The ability of retrogenic helper lineage choice. Increased efficiency of CD4 lineage ThPOK expression to only partially reprogram peripheral choice of MHCI-specific thymocytes due to augmented CD8 cytotoxic T cells into the CD4 helper T cell supports TCR signaling in ThPOK transgenic mice supports this this possibility [30]. Interestingly, all three transgenic notion [31]. Such a temporal target gene accessibility lines expressed higher amount of ThPOK compared to model may explain incomplete modulation of helper endogenous ThPOK levels observed in CD4+ T cells from and cytotoxic lineage genes in peripheral CD8 cytotoxic WT mice, and yet the lowest ThPOK expressing transgene T cells following enforced ThPOK expression [30] or in (ThPOK-H transgene) caused partial CD8 to CD4 lineage developing thymocytes with impaired Runx function redirection. As expected Runx3 was suppressed in the due to compound deficiency of Tel/Groucho proteins
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