The mechanisms and consequences of T cell activation, with reference to signaling,

differentiation, and memory

The three primary purposes of the immune system are the detection and ensuing eradication
of foreign antigens, the establishment of immunological tolerance, and memory increase to
self-antigens. The majority of the lymphocyte populace consists of T-lymphocytes, natural
killer cells (NK cells), and B-lymphocytes. T lymphocytes, that mediate cell - mediated
immunity, and B lymphocytes, that mediate humoral immunity, offer adaptive immunity.
Also with the intrinsic immune system, these cells work in close collaboration. Natural killer
T cells (NKT cells) and natural regulatory cells are a tiny subset of CD4+ cells that are
already distinct differentiated cells when they are released from the thymus.

T-lymphocytes primarily consist of CD8+ and CD4+ T cells. Once getting stimulated and
differentiating into various effector subgroups, CD4+T cells perform a vital part in modifying
immune reaction through the production of certain cytokines. The stimulation of innate
immune system cells, cytotoxic T, cells B cells, and nonimmune cells is one of the many
functions carried out by CD4+T cells. They are also essential in suppressing immunological
response. Moreover the conventional T-helper 2 (Th2) and T-helper 1 (Th1) cell subsets, new
subsets of CD4+ cells have been identified through continuing research. These include
induced regulatory type 1 cells (Tr1), follicular helper T cells (Tfh), T-regulatory cells (Treg),
Th17 cells (Th9), and T-helper 9 cells (Th9). The development of the various lineages is
regulated by a complex network of specific transcription factors and cytokine signalling,
followed by epigenetic modifications.

The naive cells undergo the first stage of their development as a result of the antigenic
stimulation caused by the contact of CD4 and TCR as co-receptor protein complexes together
with the antigen-MHC II complex structure, which is given by proficient antigen presentation
cells (APCs). An array of downstream signalling pathways are ultimately responsible for
naive cell production and diversification into specific effector cells. These pathways are
triggered as a result of TCR and CD3 activation. The microenvironment's cytokine profile,
antigen load, APC type, and amounts of costimulatory molecules all have an impact on
lineage-specific differentiation. Due to their greater capacity to dendritic cells (DCs), activate
naive T cells, are considered to be the most important APCs.
Dendritic cells become activated when pathogenic antigens are identified by pattern
recognition structures present on the cell surface such as the intracellular antigen sensing
receptors like the nucleotide oligomerization domain (NOD)-like receptors. The
differentiation lineage is obstructed by the several subgroups that make up DCs. In mice,
CD8+ DC are linked with Th1 differentiation through the production of IL-6 and IL-12,
whereas CD8 subsets are associated with Th2 differentiation. Costimulatory signals, which
promote differentiation and proliferation, amplify TCR signals. The central co-stimulatory
receptor, CD28, is expressed on all naive T cells. In response to DC activation, the CD28
ligands on DC, CD86 (B7-2), and CD80 (B7-1) are elevated. Another less efficient co-
stimulatory molecule is a part of the TNF receptor family called CD28 homolog driven co-
stimulator (ICOS) (4-1BB, CD27, and OX-40). The first suppliers of cytokines are the innate
immune cells, which include APCs as well as other APC family members. As a consequence
of a few of the cytokines the differentiated cells make functioning in a positive feedback
cycle, the proliferation and response may then be somewhat enhanced. Studies have also
unveiled a complex cell surface assembly that contains changeable proteins designated α and
β and molecules responsive to the antibodies targeting the non-polymorphic CD3 proteins
(formerly thought to be three polypeptides, δ, γ, and ε).

Tyrosines in the CD3 proteins that fall within a specific motif or domain present in CD3, ε, γ,
and δ, and in replicates within each ζ chain and also found in important immunoreceptors on
other immune cell lineages, are some of the most alluring candidates for finding tyrosine
substrates for protein tyrosine kinases. The immunoreceptor tyrosine-based activation motifs
(ITAMs), as they were later known, are characterized by two tyrosines flanking a string of
amino acids, including important leucine/isoleucines, along with stereotypical spacing. It has
been shown by multiple research groups that the ITAM tyrosines are actually phosphorylated
after TCR ligation, but it has been difficult to determine the significance of this
posttranslational change for TCR function. Several researchers have developed chimeric
molecules by joining the cytoplasmic regions of distinct CD3 chains to cytoplasmic and
membrane spanning domains from other proteins because the CD3 proteins could not be
produced without the chains. Then, T cell lines chosen for TCR loss were transfected with
these cDNAs in chimeric proteins. All known TCR-mediated signaling processes that result
in cellular activation were recapitulated by antibody binding of the chimeras' extracellular
region. Phosphorylation of the tyrosines of the CD3 ITAMs was shown to be an essential and
early step for TCR-mediated T cell activation by the fact that mutation of the important
ITAM tyrosines (or modifying their spacing) rendered the chimeras incapable of activating
the cells.

Therefore, it was hypothesized that the ITAMs' tyrosine phosphorylation might operate as
receptor sites for associations with other proteins. In fact, it was quickly discovered that
phosphorylated CD3ζ (and later additional ITAM-containing proteins) served as a site for the
recruitment of a 70 kDa phosphoprotein, later identified as ZAP-70 (ζ-associated protein of
70 kDa) PTK, a member of the syk kinase family. Thus, a hypothesis that TCR activation
caused src PTK activity, which in turn caused ITAM phosphorylation and ZAP-70
recruitment, began to take shape. This changed the TCR, which did not have an inherent
enzymatic function, into an active PTK with the capacity to phosphorylate a variety of
substrates and produce a variety of signal cascade that, when properly combined with signals
produced from other co-receptors, result in T cell activation.

Effector functions: Th1 cells are linked to organ-specific autoimmunity and are engaged in
the eradication of intracellular infections. They primarily release IL2, IFN, and lymphotoxin
α (Lfα). IL2 encourages CD8+ T cell multiplication and the development of a cytolytic
phenotype. In addition to its function as a T cell growth factor, it has been discovered that
IL2 helps to ensure a strong secondary immunological response by encouraging the formation
of CD8+ memory cells following antigen priming. The stimulation of mononuclear
phagocytes, such as macrophages and microglial cells, results in increased phagocytic
activity and is dependent on IFN. Lfα belongs to the TNF superfamily. Affinity for Lfα is
linked to autoimmune conditions. Experimentally encephalitis caused by the autoimmune
response has been found to be prevented by Lfα depletion. Th2 cells produce immune
responses to extracellular parasites, such as helminths, and are crucial in the development and
maintenance of allergic disorders such as asthma. The important effector cytokines are
amphiregulin, IL4, IL5, IL9, IL13, IL10, and IL25. IL10, IL35, and TGF-β, are the primary
effector cytokines of CD4+ cells. IL10 is a potent inhibitory cytokine that can control
proinflammatory responses, which reduces the amount of tissue damage caused by
inflammation. The substantial suppression of IgE production by IL10 and TGF-β
demonstrates the importance of these molecules in reducing allergic inflammation.

The epigenetic influence of the existing and likely unique subsets of CD4+T cells and their
procedure and methods of functioning will become better understood via further research,
providing clinicians with new tools to combat immune-mediated disorders.