Abstract
Adaptive immunity in homeotherms depends greatly on CD4+ Th cells which release cytokines in response to specific antigen stimulation. Whilst bony fish and poikilothermic tetrapods possess cells that express TcR and CD4-related genes (that exist in two forms in teleost fish; termed CD4-1 and CD4-2), to date there is no unequivocal demonstration that cells equivalent to Th exist. Thus, in this study we determined whether CD4-1+ lymphocytes can express cytokines typical of Th cells following antigen specific stimulation, using the zebrafish (Danio rerio). Initially, we analyzed the CD4 locus in zebrafish and found three CD4 homologues, a CD4-1 molecule and two CD4-2 molecules. The zfCD4-1 and zfCD4-2 transcripts were detected in immune organs and were most highly expressed in lymphocytes. A polyclonal antibody to zfCD4-1 was developed and used with an antibody to ZAP70 and revealed double positive cells by immunohistochemistry, and in the Mycobacterium marinum disease model CD4-1+ cells were apparent surrounding the granulomas typical of the infection. Next a prime-boost experiment, using human gamma globulin as antigen, was performed and revealed for the first time in fish that zfCD4-1+ lymphocytes increase the expression of cytokines and master transcription factors relevant to Th1/Th2-type responses as a consequence of boosting with specific antigen.
Highlights
T helper (Th) cells play a key role in adaptive immunity by secreting cytokines that initiate and activate downstream effector mechanisms
Th responses are well studied in mammals but very little is known about when such responses arose during the evolution of adaptive immunity, or whether Th cells equivalent to Th subtypes, such as Th1, Th2 and Th17 exist in lower vertebrates
CD4 molecules contribute to T cell activation by influencing the activity of the TcR-antigen-MHC II interaction and recruiting the coreceptor-bound cytoplasmic protein tyrosine kinase to the TcR signaling complex [55, 56]
Summary
T helper (Th) cells play a key role in adaptive immunity by secreting cytokines that initiate and activate downstream effector mechanisms. Th1 and Th2 cells were discovered initially [5] but other recently characterized effector Th subpopulations include Th9 [6], Th17 [7], Th22 [8] and T follicular helper (Tfh) [9] cells. Naïve CD4+ cells differentiate into the different subpopulations after antigen stimulation, dependent upon the cytokine milieu that drives expression of master transcription factors associated with each Th subset [3]. Whilst these recent advances tell us a lot about CD4+ Th cell plasticity and role in immunity and disease states in mammals, we know very little about the Th cell populations that may exist in other vertebrate groups
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